Abstract
The tumor microenvironment is a dynamic ecosystem of stromal and immune cells that, under the influence of cancer cells, govern biochemical signaling, mechanical signaling via production and remodeling of the extracellular matrix (ECM), formation of vascular networks, and ultimately promotion of tumor growth. In breast cancer, hormone receptor-mediated signaling is a key coordinator of cancer cell proliferation and invasiveness not only through cell-autonomous means but also via cancer cell–stroma cross-talk. In the absence of hormone receptors, a different microenvironment landscape emerges, which comes with its own challenges for therapy. This review summarizes the current knowledge regarding the associations of hormone receptor profiles with composition of the microenvironment, how hormones directly influence stromal cells, immune cells and cells associated with the vasculature, and the paracrine mechanisms that lead to the formation of a tumor-promoting ECM.
Introduction
The nuclear receptor superfamily consists of as many as 49 members. This includes those cognate for classical steroid hormones, as well as adopted and orphan nuclear receptors, for which definitive ligands are still under investigation or unknown, identified in studies regarding metabolism, diabetes, osteoporosis, aging, and more (Margolis et al. 2005).
In normal mammary development, estrogen and progesterone are essential for proliferation and differentiation via binding to the estrogen receptor (ER) and progesterone receptor (PR), respectively. The bifurcation of terminal end buds in mice or terminal ductal lobular units in humans is estrogen driven and ductal elongation and lateral branching is dependent on ERα, and ERβ and the androgen hormone receptor (AR) also contribute to control of ductal growth in puberty. Whilst development is exquisitely sensitive to estrogen signaling, only a subset of mammary epithelial cells are required to express ERα to exert functional control. Given that the epithelial tree branches into the mammary microenvironment, becoming completely surrounded by it, precise communication between epithelia and stromal cells is important. ERα-regulated production of amphiregulin by epithelial cells activates epidermal growth factor receptor in the mammary stroma, recruiting macrophages and eosinophils to remodel tissue allowing for branching to occur (Hansen & Bissell 2000, Need et al. 2014). Furthermore, ER is required within the stroma, as stromal cell-specific depletion of ER completely ablates epithelial outgrowth in transplantation studies. This highlights the essential role of paracrine communication between epithelia and stroma in development of the mammary gland (Cunha et al. 1997).
Breast cancer is a highly heterogenous disease that varies at the patient, pathological, and molecular levels. The main subtypes of breast cancer according to their molecular portraits – luminal A, luminal B, human epidermal growth factor receptor 2 (HER2, also known as ERBB2) enriched and basal-like – are typified by nuclear hormone receptor profiles that dictate pathology as well as treatment regime. The hormone receptors used in diagnosis are ER and PR; however AR also plays a role in breast cancer pathobiology. Luminal A tumors are classified as ER positive (+) and/or PR+ and HER2 negative (−) and present with a low level of proliferation (low Ki67 levels). Luminal B tumors are classified as ER+ and/or PR+ and/or HER2+ and have a high level of proliferation (high Ki67 levels). HER2-enriched cancers are ER−PR−HER2+, whilst basal-like tumors are ER−PR−HER2−, also known as triple-negative breast cancers (TNBCs) (Perou et al. 2000, Loibl et al. 2021). These hormone receptor-negative tumors are frequently associated with poor differentiation. Some tumors encompass more than one of these profiles, with phenotypes straddling luminal and HER2+, as well as triple-negative non-basal subgroups (Kennecke et al. 2010).
Agents that target hormone receptor signaling, including selective ER modulators (SERMs) or degraders and aromatase inhibitors, have been critical in controlling patient mortality since their development. Frontline systemic treatment of postmenopausal patients with hormone receptor-positive HER2− breast cancer is generally targeted endocrine therapy (for 5–10 years), with cytotoxic chemotherapy as a third-line strategy; however, the optimal therapy sequence for these patients is not clearly defined (Loibl et al. 2021). In ER+ disease, patients with invasive lobular pathology have shown a better survival response to adjuvant hormonal therapy than those with invasive ductal carcinoma (Rakha et al. 2008). Hormone receptor-negative HER2+ and TNBC tumors do not often respond to endocrine therapy. The treatment of HER2+ breast cancer patients using anti-HER2 monoclonal antibody therapy (generally in combination with chemotherapy) has transformed disease management, whilst TNBC is still largely managed by chemotherapy, though many clinical trials are currently ongoing to test immunotherapy for these patients. Other agents such as poly(ADP-ribose) polymerase(PARP) inhibitors, checkpoint inhibitors, and phosphoinositide 3 kinase (PI3K) inhibitors may be employed on an individual basis (Loibl et al. 2021).
Downstream of hormone receptors in breast cancer cells, located both in the nucleus and in the cytoplasm, a multitude of pathways are activated. For instance, upon estrogen binding, ERs dimerize, recruit co-activators to form a functional ER complex, and act as transcription factors by binding to estrogen response elements (EREs) within promoters of target genes. ER functioning as a co-activator can also regulate the transcription of genes lacking an ERE. Signaling cascades triggered by estrogen include protein kinase pathways such as mitogen-activated protein kinase (MAPK), PI3K/protein kinase B (Akt), and protein kinase A as well as genes that regulate proliferation and cycling such as c-Myc, cyclin D1, epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin-like growth factor 1 (IGF-1) (Yamaguchi 2007, Rothenberger et al. 2018). Perhaps not unsurprisingly because of the tumorigenic cascades triggered by hormone receptor signaling, a large-scale clinical study of over 16,000 postmenopausal women found that individuals receiving combined estrogen and progestin hormone replacement therapy (HRT) had significantly increased incidence of breast cancer (Chlebowski et al. 2010). Another study showed that combined HRT increased the risk of invasive lobular and lobular/ductal carcinomas but not ductal carcinomas (Li et al. 2008).
Survival estimates are significantly different between subtypes. At 5 years follow-up, patients with hormone receptor-positive breast cancer have a significantly better survival prognosis, at up to 95% compared with approximately 80% for hormone receptor-negative breast cancer (Chen et al. 2014). Analysis of archived tissue demonstrated that at 10 years follow-up, 70% of patients with luminal A were alive (the best prognosis), compared with 54% of luminal B, 48% of HER2+, and 53% of TNBC. Furthermore, the molecular expression of hormone receptors is prognostic for metastatic spread. Median survival with distant metastasis in patients with luminal A tumors was shown to be 2.2 years (again the most favorable prognosis of all subtypes), compared to 1.6 years for luminal B, 0.7 years for HER2+, and 0.5 years for TNBC. Hormone receptor-negative subtypes generally exhibit a high rate of early relapse (Kennecke et al. 2010).
The tumor microenvironment (TME) in solid cancers is a complex and dynamic ecosystem, and it has become increasingly clear that the TME and the co-opting of its constituents by cancer cells is an absolute necessity for cancer growth, invasion, and metastasis. The major stromal cell type within the TME is cancer-associated fibroblasts (CAFs), which are recruited and reprogrammed by cancer cells to support its growth. Fibroblasts are the primary producer of components of the extracellular matrix (ECM), a protein scaffold that maintains tissue structural integrity and provides a source of mechanical signals to cancer and stromal cells. The other major cell type within the breast TME is tumor-associated macrophages (TAMs), a myeloid immune cell population involved in immune surveillance that can undergo a phenotypic switch to pro-tumorigenic under the influence of cancer cells. Whilst not all covered within the scope of this review, other immune cell types present within the TME include T cells (helper T cells (Th), cytotoxic T lymphocytes (CTLs), and regulatory T cells (Tregs)), B cells, neutrophils (that can also undergo phenotype switching), myeloid-derived suppressor cells, basophils, eosinophils, mast cells, natural killer (NK) cells, and dendritic cells. These various immune cell populations have diverse spatiotemporal roles in tumor suppression and tumor promotion via immunomodulation (Boyle et al. 2020a).
Tumor cells can also hijack normal adipocytes within the stroma or neighboring fat depots via metabolic reprogramming, to generate cancer-associated adipocytes (CAAs). CAAs produce tumor-promoting metabolites as well as adipokines and other secreted factors that influence cancer cells, stromal cells, and the vasculature (Poltavets et al. 2018). However, the influence of hormones on their function is not widely known.
Lastly, the tumor and its TME are reliant on maintenance of a vasculature network that supplies the tumor with nutrients as well as a means of metastatic escape. The establishment of this is regulated by pro-angiogenic signals from cancer and stromal cells to endothelial cells (Boyle et al. 2020a). As summarized in Fig. 1, hormonal signaling and cross-talk influence the breast TME in terms of its establishment, regulation, and function in augmenting cancer growth.
The tumor microenvironment in hormone receptor-positive breast cancer. The known effects of estrogen (E) and progesterone (P) on the composition, regulation, and cross-talk of the tumor microenvironment in hormone receptor-positive breast cancers via signaling through estrogen receptor (ER) and progesterone receptor (PR). ECM, extracellular matrix; MMP, matrix metalloprotease; VEGF, vascular endothelial growth factor. Information used to generate this figure was taken from published literature, as detailed in this review.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
The tumor microenvironment in hormone receptor-positive breast cancer. The known effects of estrogen (E) and progesterone (P) on the composition, regulation, and cross-talk of the tumor microenvironment in hormone receptor-positive breast cancers via signaling through estrogen receptor (ER) and progesterone receptor (PR). ECM, extracellular matrix; MMP, matrix metalloprotease; VEGF, vascular endothelial growth factor. Information used to generate this figure was taken from published literature, as detailed in this review.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
The tumor microenvironment in hormone receptor-positive breast cancer. The known effects of estrogen (E) and progesterone (P) on the composition, regulation, and cross-talk of the tumor microenvironment in hormone receptor-positive breast cancers via signaling through estrogen receptor (ER) and progesterone receptor (PR). ECM, extracellular matrix; MMP, matrix metalloprotease; VEGF, vascular endothelial growth factor. Information used to generate this figure was taken from published literature, as detailed in this review.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
Hormonal cross-talk between breast cancer cells and stromal fibroblasts
CAFs are a mixed population that may comprise myofibroblasts, mesenchymal cells, tissue-resident fibroblasts, and fibroblasts recruited from the vasculature. In tumors derived from the polyoma middle-T murine model of breast cancer, single-cell sequencing studies have elucidated fibroblast clusters classified into categories such as activated myofibroblasts, secretory remodeling/desmoplastic CAFs, and secretory inflammatory CAFs (Valdes-Mora et al. 2021). Upon activation by tumor-derived factors including transforming growth factor beta (TGFβ), EGF, platelet-derived growth factor alpha (PDGFα) and PDGFβ, FGF, interleukins, CRELD2, and thrombospondin-2 (THBS-2), CAFs are capable of producing an array of growth signals as well as ECM components and ECM-remodeling enzymes, thereby influencing cancer growth via both biochemical and mechanical means (Boyle et al. 2020a,b).
Aromatase (encoded for by the gene CYP19A1), a key enzyme in estrogen biosynthesis mediating the conversion of androgens to estrogen, is higher in breast cancer compared to normal breast tissue and specifically higher in the stromal regions adjacent to cancer cells (Santen et al. 1997). It was demonstrated that the androgen testosterone induced ER+ breast cancer cell proliferation via its conversion by aromatase to estrogen in fibroblasts (Chottanapund et al. 2013). Aromatase expression has been shown to be stimulated and regulated by a number of factors that are induced by cancer cell–stroma cross-talk, including p53, prostaglandin E2 (PGE2), cyclooxygenase-2, tumor necrosis factor alpha (TNFα), and IL-6 and IL-11, as well as other factors secreted from breast cancer cells that remain unidentified. As an example, PGE2 is produced by breast cancer cells and other cells within the TME and stimulates the expression of aromatase in neighboring stromal fibroblasts. Via the induction of IL-6, PGE2 also activates adenyl cyclase and results in an increase in intracellular cyclic adenosine monophosphate that enhances aromatase enzymatic activity (Santen et al. 1997, Zhou et al. 2001, Yamaguchi 2007, Wang et al. 2015).
The production of estrogen by fibroblasts in turn stimulates ER signaling in breast cancer cells. When cultured in conditioned medium from breast carcinoma fibroblasts, ER+ breast cancer cells are significantly more proliferative and less apoptotic, leading to enhanced ductal hyperplasia (Dittmer et al. 2020). However, individual breast cancers vary in their fibroblasts’ ability to stimulate hormone receptors (Yamaguchi et al. 2005). Different populations of fibroblasts can influence the expression of ER and PR on breast cancer cells (Adam et al. 1994), and fibroblasts in postmenopausal patients activate ER more effectively than those in premenopausal patients (Yamaguchi et al. 2005).
CAFs may also influence sensitivity to hormone therapy. Through stimulation of integrin β1 by soluble factors and ECM proteins, CAFs are capable of inducing endocrine drug resistance in breast cancer cells via activation of the PI3K/Akt pathway and downstream IGFBP5/B-cell lymphoma(Bcl)-3 and MAPK/extracellular-signal regulated kinase (ERK)-1/2 signaling cascades (Pontiggia et al. 2012, Leyh et al. 2015).
In addition to the aforementioned factors that activate CAFs, exposure to hormones within the tumor milieu has been shown to activate fatty acid synthase within CAFs in the TME. This in turn modulates breast cancer cell lipid metabolism, enabling cancer cells to increase their uptake of lipids from the microenvironment and enhance their proliferation (Lopes-Coelho et al. 2018). Interestingly, CAFs have also been shown to secrete microRNAs within exosomes, which are taken up by breast cancer cells and control ER expression (Shah et al. 2015).
Profiling of 48 nuclear receptors in CAFs from patients with ERα+ breast tumors, compared with normal fibroblasts from adjacent breast tissue, revealed that levels of endocrine and adopted nuclear receptors were comparable between the two groups. However, the expression of orphan receptors (retinoic acid receptor) RAR-related orphan receptor alpha (ROR-α), Thyroid hormone receptor beta, vitamin D receptor, and peroxisome proliferator-activated receptor gamma (PPAR-γ) were significantly downregulated in CAFs, receptors DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), estrogen-related receptor beta, and ROR-β were only present in normal fibroblasts, and liver receptor homolog-1 (LRH-1) was only present in CAFs (Knower et al. 2013). The downregulation of the adipogenic transcription factor PPAR-γ may be responsible for mesenchymal cell differentiation down the fibroblast lineage (Meng et al. 2001). As LRH-1 transcriptionally regulates aromatase, and LRH-1 and aromatase are co-expressed in breast cancer, it has been postulated that these differentially regulated orphan receptors in fibroblast populations may play a role in mediating epithelial and stromal cell interaction (Rothenberger et al. 2018).
CAFs produce an environment rich in pro-metastatic ECM proteins and enhance the ability of ER+ breast cancer cells to metastasize to the lung in mouse models (Brechbuhl et al. 2020), potentially via the production of IL-6 (Studebaker et al. 2008). In clinical samples, the hormone receptor status of primary breast cancers is associated with CAF infiltration into metastatic sites. Luminal A and B patients display the lowest scores for CAF markers in lymph node metastases, compared to HER2+ and TNBC patients. Patients who displayed abundant lymph node CAF infiltration at diagnosis were more likely to exhibit distant metastasis to other organs, in particular the liver (Pelon et al. 2020).
Regulation of infiltrating immune cells
In the normal cycling mammary gland of premenopausal women, estrogen- and progesterone-mediated signaling in epithelial and stromal cells results in the production of colony-stimulating factor 1 (CSF-1), TGFβ, and IL-10, which recruits various immune cell populations. In the luteal phase of the menstrual cycle and during pregnancy, this promotes mammary morphogenesis but in doing so skews cellular function away from immune surveillance, and for example, macrophages favor their tissue remodeling functions and downregulate antigen-presenting markers and production of inflammatory cytokines (Need et al. 2014). The enhanced immunotolerant microenvironment may contribute to breast cancer development, and indeed, studies also suggest that estrogen promotes an immunosuppressive TME via inhibiting the anti-tumor activity of NK cells and CTLs through upregulation of proteinase inhibitor-9 (PI-9) in tumor cells (Somasundaram et al. 2020). In addition, exposure to the xenoestrogen bisphenol-A (BPA) in utero dysregulates immunoregulatory cytokine production, potentially contributing to this immunosuppressive microenvironment (Fischer et al. 2016), and likewise the use of oral contraceptives has been suggested to influence immune cell populations (Vincent & Salamonsen 2000, Isfoss et al. 2018).
The hormone receptor status of breast tumors has a strong influence on the immune infiltration profile (Fig. 2). TAMs and tumor-infiltrating lymphocytes (TILs) are discussed in more detail below, but multiple other immune cell populations are also affected. Hormone receptor-positive tumors, in particular ER+ tumors, have a higher proportion of mast cells, anti-tumor NK cells, and neutrophils compared to hormone receptor-negative tumors, and eosinophil and monocyte numbers are indicative of a good response to chemotherapy (Segovia-Mendoza & Morales-Montor 2019, Pyla et al. 2020). When comparing different pathologies of ER+ breast cancers, follicular Th cells, γδ T cells, and macrophages are less abundant in invasive lobular carcinoma, compared with invasive ductal carcinomas that have higher frequencies of B cells, monocytes, and CTLs (Desmedt et al. 2018).
The immune infiltrate in breast cancer based on hormone receptor profile. The immune infiltrate in hormone receptor-negative breast tumors is different from that in hormone receptor-positive tumors. Hormone receptor-positive tumors have a high abundance of mast cells, natural killer (NK) cells, neutrophils, and eosinophils. Hormone receptor-negative tumors have a high abundance of M2-like macrophages, dendritic cells, mast cells, γδ T cells, regulatory T cells (Tregs), and neutrophils and a high infiltration of cytotoxic T lymphocytes (CTLs), helper T (Th) cells, and B cells is associated with a better prognosis. Size of the cells indicates high or low abundance, whilst color indicates prognosis. Green denotes cell populations whose presence is associated with a favorable outcome and red denotes populations associated with a poorer outcome. Yellow denotes cell populations with lower abundance that do not have a definitive reported prognostic role. PI-9, proteinase inhibitor-9.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
The immune infiltrate in breast cancer based on hormone receptor profile. The immune infiltrate in hormone receptor-negative breast tumors is different from that in hormone receptor-positive tumors. Hormone receptor-positive tumors have a high abundance of mast cells, natural killer (NK) cells, neutrophils, and eosinophils. Hormone receptor-negative tumors have a high abundance of M2-like macrophages, dendritic cells, mast cells, γδ T cells, regulatory T cells (Tregs), and neutrophils and a high infiltration of cytotoxic T lymphocytes (CTLs), helper T (Th) cells, and B cells is associated with a better prognosis. Size of the cells indicates high or low abundance, whilst color indicates prognosis. Green denotes cell populations whose presence is associated with a favorable outcome and red denotes populations associated with a poorer outcome. Yellow denotes cell populations with lower abundance that do not have a definitive reported prognostic role. PI-9, proteinase inhibitor-9.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
The immune infiltrate in breast cancer based on hormone receptor profile. The immune infiltrate in hormone receptor-negative breast tumors is different from that in hormone receptor-positive tumors. Hormone receptor-positive tumors have a high abundance of mast cells, natural killer (NK) cells, neutrophils, and eosinophils. Hormone receptor-negative tumors have a high abundance of M2-like macrophages, dendritic cells, mast cells, γδ T cells, regulatory T cells (Tregs), and neutrophils and a high infiltration of cytotoxic T lymphocytes (CTLs), helper T (Th) cells, and B cells is associated with a better prognosis. Size of the cells indicates high or low abundance, whilst color indicates prognosis. Green denotes cell populations whose presence is associated with a favorable outcome and red denotes populations associated with a poorer outcome. Yellow denotes cell populations with lower abundance that do not have a definitive reported prognostic role. PI-9, proteinase inhibitor-9.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
In HER2+ tumors, the dominant populations are dendritic cells, mast cells, γδ T cells, Tregs, and neutrophils, and in these tumors, these populations are associated with negative prognosis and poor survival (Segovia-Mendoza & Morales-Montor 2019). In ER− tumors and metastases, the proportions of anti-tumor immune populations are diminished relative to ER+, in favor of immunosuppressive populations such as Tregs and TAMs that are associated with a worse prognosis (Segovia-Mendoza & Morales-Montor 2019, Williams et al. 2021). In addition, HER2+ or TNBC cells are significantly less susceptible to NK cell killing than hormone receptor-positive breast cancer cells (Goldberg et al. 2021).
Tumor-associated macrophages
The inherent function of TAMs is tumor surveillance and suppression, and production of pro-inflammatory factors. However, it has become clear that TAMs acquire immunosuppressive and tumor-promoting roles, generally following phenotypic plasticity toward an anti-inflammatory ‘M2’ state from the pro-inflammatory ‘M1’ state. Upon their recruitment and/or polarization induced by many cancer cell-derived factors, TAMs secrete a range of interleukins, growth factors, cytokines, and chemokines that directly promote tumor growth as well as indirectly via immune restraint, activation of CAFs, and ECM production (Boyle et al. 2020a).
The balance of estrogen and progesterone mediates macrophage numbers and inflammatory phenotype in the mammary gland, leading overall to an immunotolerant environment (Need et al. 2014). In breast cancer, whilst extensive TAM infiltration is associated with cancer aggressiveness regardless of hormone receptor status, infiltration differs based on hormone receptor-stratified subtype and is significantly lower in luminal A tumors compared to luminal B and hormone receptor-negative tumors (Campbell et al. 2011, Gwak et al. 2015). As with CAFs, TAMs have been demonstrated to not only be a target of estrogen but also express abundant aromatase. Precursor monocytes, on the other hand, express little to no aromatase. Macrophages can therefore themselves produce estrogen to influence breast cancer growth and the TME, including autocrine regulation (Mor et al. 1998).
In addition to influx and polarization, estrogen modulates macrophage function – including nitric oxide release, lipid metabolism, phagocytic activity, and production of antioxidant enzymes and anti-inflammatory factors – as well as macrophage survival and activation (Segovia-Mendoza & Morales-Montor 2019). In ER+ breast cancer, estrogen-stimulated production of chemokines CCL2 and CCL5 from cancer cells was associated with TAM influx, which in turn promoted cancer cell dissemination (Svensson et al. 2015). Macrophages in breast cancers also express AR and are associated with more aggressive tumor growth in the presence of androgens (Yamaguchi et al. 2021). Macrophages cultured in the presence of cancer cells, regardless of receptor expression, are more tumor-promoting than when cultured alone; however, macrophage activation varies based on the context of ER+ vs TNBC. In non-contact co-culture with TNBC cells, macrophages had significantly higher expression of markers associated with an M2 phenotype compared to macrophages co-cultured with ER+ breast cancer cells (Hollmen et al. 2015).
Macrophages are associated with tamoxifen resistance in breast cancer patients (Xuan et al. 2014) and contribute to the development of endocrine drug resistance via the activation of the PI3K/Akt pathway. This has been shown to be mediated by the secretion of the chemokine CCL2 upon polarization to an M2 phenotype (Li et al. 2020). Another study reported that increased M1 TAM levels in hormone receptor-positive HER2− patients was associated with a positive response to neoadjuvant chemotherapy; however post-chemotherapy, macrophages had gene signatures associated with M2 polarization relative to M1 (Waks et al. 2019). These results implicate M2 macrophages in chemoresistance in hormone receptor-positive tumors. Interestingly, breast cancer cells that have acquired aromatase inhibitor resistance have been found to produce the adipokine leptin, which acts upon macrophages in the TME to regulate their motility and profile, activating the nuclear factor kappa B and p38/ERK pathways to produce IL-18 and IL-8, respectively (Cao et al. 2016, Li et al. 2016, Gelsomino et al. 2020). In turn, TAMs promoted the migration and invasion of breast cancer cells (Li et al. 2016), suggesting a paracrine loop of macrophage activity and endocrine therapy resistance in breast cancer.
Tumor-infiltrating lymphocytes
Whilst overall most breast tumors display a relatively immune-suppressed microenvironment (Waks et al. 2019), the composition of TILs within breast tumors is associated with hormone receptor profile (Fig. 2). CD4+ Th1 cells, B cells, and CD8+ CTLs are significantly more abundant in ER− breast tumors relative to ER+ (Dannenfelser et al. 2017), which have a strong proportion of NK cells and neutrophils (Segovia-Mendoza & Morales-Montor 2019). In the more aggressive HER2+ and TNBC subtypes, a high TIL count (in particular infiltration of CD8+ CTLs, which are present in approximately 60% of these tumors) is associated with a survival benefit and increased anti-tumor immunity. Conversely, in luminal HER2– breast cancers, high TIL count predicts a worse outcome (Stanton & Disis 2016, Denkert et al. 2018, Rothenberger et al. 2018, Katsuta et al. 2021). Whilst globally higher TIL values are associated with hormone receptor negativity, within ER+ disease various pathologies display differences in TIL proportions. TILs are positively associated with proliferation of ER+ HER2− cells in both invasive ductal and lobular carcinomas but are also shown to be increased in non-classic lobular cancers and decreased in alveolar, relative to classic lobular carcinoma (Desmedt et al. 2018).
Estrogen affects the size, maturation and development of T cells via ERα signaling. Estrogen predisposes Th cells in the blood to a Th2 phenotype during the luteal phase of the menstrual cycle, with increased IL-4 production and anti-inflammatory phenotype whilst inhibiting the production of Th1 pro-inflammatory cytokines (Faas et al. 2000, Rothenberger et al. 2018, Segovia-Mendoza & Morales-Montor 2019). It can also mediate differentiation to an immunosuppressive Th17 phenotype (Lelu et al. 2011).
Treg cells are increased in the blood during the follicular phase of the menstrual cycle (Arruvito et al. 2007). Their abundance is enhanced by both estrogen and progesterone, and estrogen induces gene expression of the major Treg transcription factor FOXP3 (Polanczyk et al. 2004, Prieto & Rosenstein 2006, Lee et al. 2012). The presence of Treg cells in breast cancer generally denotes a poor outcome and heightened risk of relapse due to enhanced immunosuppression and immune escape, although their prognostic value remains unclear. For instance, although increased Tregs in ER+ breast cancer is predictive of poor survival, Treg infiltration is more strongly associated with expression of HER2 and ER negativity (Mahmoud et al. 2011, Qian et al. 2017, Glajcar et al. 2019), with a trend toward higher proportions in TNBC (Savas et al. 2018). It has been postulated that their function may differ depending on ER and HER2 expression status as well as CTL infiltration (Liu et al. 2014).
Estrogen stimulates nuclear ER in B lymphocytes, increasing immunoglobulin production. As well as activating and promoting survival of B cells, the subsequent increase in immunoglobulin M levels is important for the anti-tumor functions of B cells within the TME (Segovia-Mendoza & Morales-Montor 2019). At a global scale however, B lymphocytes are associated with hormone receptor negativity. In HER2+ and TNBC patients, there is a significant population of B TILs compared to normal breast tissue, which actively produce humoral immune responses to tumor cells (Garaud et al. 2019). Therefore, regardless of hormone receptor status, higher levels of B cell infiltration are predictive of a better outcome (Denkert et al. 2010).
Compared to patients with hormone receptor-positive breast cancer where a survival advantage is not conferred, TNBC patients with high levels of CD8, and CTL effector proteins granzyme B and CXCL10, have a significantly better survival prognosis (Savas et al. 2018, Katsuta et al. 2021). Potentially, immune escape in hormone receptor-positive breast cancers may contribute to recurrence. Estrogen has been shown to induce the production of PI-9, which inhibits granzyme B used by CTLs to mediate cell killing (Jiang et al. 2006). Expression of the immune checkpoint marker programmed death ligand-1 (PD-L1) is associated with CTL infiltration (Stanton & Disis 2016), and in hormone responsive cancers, estrogen modulates PD-L1 expression and also augments the ability of Tregs to exhaust anti-tumor CTLs via upregulation of programmed death-1 (PD-1) levels on Tregs (Polanczyk et al. 2007, Rothenberger et al. 2018, Goldberg et al. 2021). In TNBC, which has high levels of PD-L1 expression compared to hormone receptor-positive subtypes, anti-PD-L1 and anti-PD-1 immune checkpoint blockade has been used clinically in combination with chemotherapy to improve survival outcomes (Stanton & Disis 2016, Goldberg et al. 2021).
Perhaps unsurprisingly, TIL populations are altered in patients that have received chemotherapy and endocrine therapy. As examples, studies have demonstrated that patients treated with aromatase inhibitors have significantly decreased Treg numbers and increased CD4+ T cell infiltration (Generali et al. 2009, Hazlett et al. 2021), and anti-estrogens can enhance host immunity and promote ER+ tumor cell killing by CTLs (Baral et al. 1997). Another report showed that Treg and CD8+ populations were decreased in patients with luminal HER2− tumors receiving neoadjuvant therapy, in favor of increased myeloid populations (including macrophages and dendritic cells). This study also noted that in tumors with detectable but low expression of ER and PR, which are still classed as hormone receptor-positive, response to immunotherapy may be better predicted by grouping patients together with TNBC to better tailor treatments and outcomes (Waks et al. 2019). Indeed, evidence strongly suggests that pre-therapy immune infiltrate, as well as PD-L1 levels, can predict response to treatment and overall prognosis (Stanton & Disis 2016, Takada et al. 2019, Loibl et al. 2021). Harnessing the immune profile as an additional clinical characterization may therefore enhance the efficacy of targeted immune therapy.
Cooperation between hormonal signaling and the ECM
The ECM, which is made up of structural and matricellular proteins including collagens, fibronectin, and proteoglycans, functions to provide integrity for tissues and organs as well as a source of mechanical signals and biochemical signaling molecules (chemokines, cytokines, and growth factors) that are released or sequestered as it remodels (Poltavets et al. 2018). Production of collagens and their structural organization, as well as expression of collagen-remodeling enzymes, are heavily influenced by hormonal reproductive cycles and involution in the normal breast (Guo et al. 2022). In addition, a recent systematic review highlighted strong associations between the use of HRT, in particular combined HRT, and higher mammographic density (Azam et al. 2020), which is caused by dense fibrous stroma within the mammary gland and is a risk factor for breast cancer (Boyd 2013). During the process of tumorigenesis and cancer growth, the ECM is frequently remodeled to enhance its stiffness through the cross-linking of collagen that forms the bulk of the structure and increased production of ECM proteins, predominantly by stromal fibroblasts as well as macrophages. Enhanced ECM stiffness in solid tumors promotes tumor growth, epithelial–mesenchymal transition, invasion, and metastasis via activation of mechanotransduction signaling within cancer and stromal cells (Boyle et al. 2020a) and via modulation of the tumor immune microenvironment by influencing immune cell recruitment (Kolesnikoff et al. 2022).
Fibrillar collagens type I, III, and V and non-fibrillar collagens type VI, VII, XIV, and XV make up greater than 99% of the total collagens within the mammary gland (Guo et al. 2022). Collagen I, a major structural component of the ECM in the mammary gland, is significantly altered during neoplasia, and its abundance and organization has been implicated in breast cancer progression, invasion, and metastasis (Deak et al. 1991, Kauppila et al. 1998, Provenzano et al. 2006, Liu et al. 2018, Song et al. 2022). Increased COL1A1 levels have been associated with poor survival in patients with ER+ breast cancer (Liu et al. 2018). Likewise, in murine models of ER+ mammary cancer, estrogen-mediated signaling is associated with significant increases in expression of collagen I and a suite of matricellular proteins (Jallow et al. 2019). Collagen III is also highly expressed and altered in breast cancers (Deak et al. 1991, Kauppila et al. 1998, Song et al. 2022), and collagen V, a minor fibrillar collagen, is often co-expressed and co-assembled with collagen I into heterotypic fibrils (Mak et al. 2016) and is associated with breast cancer progression and prognosis (Ren et al. 2018).
To investigate the expression of fibrillar collagens in the context of hormone receptor status within human samples, breast cancer patient microarray data were evaluated from The Cancer Genome Atlas (TCGA) (Cancer Genome Atlas 2012) and The Molecular Taxonomy Of Breast Cancer International Consortium (METABRIC) (Curtis et al. 2012) resources, made publicly available through the Oncomine mining platform (Rhodes et al. 2007). The TCGA dataset analyzed consisted of 593 samples, and the METABRIC dataset consisted of 2136 samples, spanning normal breast, in situ breast cancer, and invasive breast cancer. Samples lacking data on hormone receptor profile were excluded, and the remaining patients were grouped as hormone receptor-positive (ER+ and/or PR+) or triple-negative (ER− PR− HER2−). Analysis of both datasets demonstrated that in hormone receptor-positive breast cancers, collagen type I levels (as shown by the expression of COL1A1 and COL1A2) are significantly higher than in TNBC (Fig. 3A and B). Further interrogation of the the METABRIC dataset showed that fibrillar collagen type III (COL3A1) and collagen type V (COL5A1) levels are also higher in hormone receptor-positive cancers compared to TNBC (Fig. 3C and D). Together, these data suggest that hormone receptor expression has a significant influence on the levels of fibrillar collagens within breast cancers.
Collagen levels in human breast cancer patient samples stratified by hormone receptor profile. (A, B) Expression (median-centered intensity) of COL1A1 (A) and COL1A2 (B) mRNA in estrogen and/or progesterone hormone receptor-positive (HR+) samples compared to triple-negative breast cancer (TNBC) samples from the TCGA and METABRIC datasets. (C, D) Expression (median-centered intensity) of COL3A1 (C) and COL5A1 (D) mRNA in HR+ samples compared to TNBC samples from the METABRIC dataset. Data are median ± IQR, analyzed by Mann–Whitney tests. TCGA: n = 273 HR+, 49 TNBC. METABRIC: n = 1556 HR+, 250 TNBC. **P < 0.01, ***P < 0.001, ****P < 0.0001.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
Collagen levels in human breast cancer patient samples stratified by hormone receptor profile. (A, B) Expression (median-centered intensity) of COL1A1 (A) and COL1A2 (B) mRNA in estrogen and/or progesterone hormone receptor-positive (HR+) samples compared to triple-negative breast cancer (TNBC) samples from the TCGA and METABRIC datasets. (C, D) Expression (median-centered intensity) of COL3A1 (C) and COL5A1 (D) mRNA in HR+ samples compared to TNBC samples from the METABRIC dataset. Data are median ± IQR, analyzed by Mann–Whitney tests. TCGA: n = 273 HR+, 49 TNBC. METABRIC: n = 1556 HR+, 250 TNBC. **P < 0.01, ***P < 0.001, ****P < 0.0001.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
Collagen levels in human breast cancer patient samples stratified by hormone receptor profile. (A, B) Expression (median-centered intensity) of COL1A1 (A) and COL1A2 (B) mRNA in estrogen and/or progesterone hormone receptor-positive (HR+) samples compared to triple-negative breast cancer (TNBC) samples from the TCGA and METABRIC datasets. (C, D) Expression (median-centered intensity) of COL3A1 (C) and COL5A1 (D) mRNA in HR+ samples compared to TNBC samples from the METABRIC dataset. Data are median ± IQR, analyzed by Mann–Whitney tests. TCGA: n = 273 HR+, 49 TNBC. METABRIC: n = 1556 HR+, 250 TNBC. **P < 0.01, ***P < 0.001, ****P < 0.0001.
Citation: Journal of Molecular Endocrinology 70, 3; 10.1530/JME-22-0174
The amount of collagen as well as its organization can influence mechanical signaling within tumor and stromal cells. Regardless of ER or PR status, enhanced collagen alignment in breast cancer patients is an independent prognostic indicator of poor survival (Conklin et al. 2011); however, the alignment of collagen fibers is significantly altered upon estrogen stimulation (Jallow et al. 2019). This is likely due to stromal cell activity. For example, in the developing mammary gland, estrogen-mediated CSF-1 production recruits macrophages that potentially interact with fibroblasts to remodel collagen into fibrillar bundles around the growing epithelial ducts and terminal end buds, determining ductal shape and extent of growth (Ingman et al. 2006, Fleming et al. 2012).
Steroid hormone signaling is important in cell–ECM interactions, leading to enzymatic remodeling and subsequent development of mammary hyperplasia. The balance of PR isoforms regulates basement membrane integrity and ECM composition, influencing laminin, collagens, and matrix metalloproteases (MMPs) (Simian et al. 2009), whilst ER status influences matrix proteoglycan composition and spatial distribution (Skandalis et al. 2014). Using ovariectomized mice, it was also shown that estrogen and progesterone regulate levels of fibronectin in the mammary gland stroma (Woodward et al. 2001), and in endometrial tissue, progesterone (including when delivered as a contraceptive) inhibits the production of matrix remodeling enzymes MMP1, MMP2, and MMP9 (collagenase, gelatinase A, and gelatinase B, respectively) (Marbaix et al. 1992, Vincent & Salamonsen 2000). Exposure to xenoestrogens such as BPA during fetal development significantly impacts mammary gland morphogenesis through the disruption of stromal collagen, versican, and tenascin C (Wadia et al. 2013) and can induce mammary neoplasia (Paulose et al. 2015).
Expression of integrins, key detectors of changes in the ECM, has also been suggested to be regulated by ER and PR expression on cancer cells. For example, the integrin α2 gene contains EREs, and the integrin α6 promoter contains progesterone response elements. Integrin α2β1 expression and function is higher in ER+ breast cancer cells compared to ER– cells and is associated with the production of MMP1 (Hansen & Bissell 2000). Estrogen and progesterone have also been suggested to regulate levels of integrin α5β1, which is stimulated by fibronectin, in the adult mammary gland (Woodward et al. 2001).
In turn, the composition of the ECM can influence hormone function. It was demonstrated that ER+ breast cancer cell lines had impaired estrogen-induced proliferation when attached to laminin due to a decrease in ERE-mediated transcription, potentially via regulation of signaling through the laminin-specific integrin α6 on breast cancer cells (Woodward et al. 2000, Haslam & Woodward 2003). This was not the case when cells were cultured on collagen I, collagen IV, or fibronectin (Woodward et al. 2000), and indeed in the context of stiff collagen I matrices vs compliant matrices, hormone-stimulated proliferation and invasion are enhanced (Barcus et al. 2015). It was further demonstrated that in mice co-implanted with ER+ breast cancer cells and soluble collagen I or laminin, estrogen-induced tumor growth was significantly lower in laminin-containing tumors compared to collagen I (Haslam & Woodward 2003).
Laminin has also been shown to cooperate with prolactin (the lactogenic hormone required for alveologenesis of the mammary gland and production of milk during lactation). Laminin-111 remodels mammary epithelium into polarized acini, exposing the prolactin receptor and leading to sustained activation of STAT-5 that induces the production of milk proteins such as β- and γ-caseins (Xu et al. 2009). As such, integrated ECM and hormone signals cooperate to allow proper functioning and differentiation of mammary epithelial cells via the regulation of transcription factor activity. Furthermore, it was demonstrated that laminin-induced signaling through integrin β1 influenced functional differentiation of mammary epithelial cells to milk protein (β-casein)-producing cells, with stiffer substrata and lower laminin content (relative to collagen I) leading to a downregulation in milk protein production and a switch from normal mammary function to pro-tumorigenic. The laminin-induced cell plasticity was found to be mediated in part through the actomyosin cytoskeleton via a decrease in actin polymerization and myosin II activity downstream of integrin activation (Alcaraz et al. 2008).
It is therefore evident that hormone signals and the ECM cooperate to promote growth of breast cancers in a positive feed-forward fashion. Using a model of elevated collagen deposition (and therefore stiffness), growth of syngeneic murine ER+ mammary tumors was shown to be enhanced by agonistic treatment with the estrogen analog tamoxifen delivered via implantation of a 25 mg tamoxifen citrate pellet, and the size of lung metastases was increased in the presence of estrogen (Jallow et al. 2019). Likewise, upon culture in stiff matrices, estrogen and prolactin cross-talk enhances mechanotransduction signaling in ER+ breast cancer cells, potentiating a switch from homeostatic hormone signaling through JAK-2/STAT-5 to pro-tumorigenic through FAK/SFK/ERK1/2. This results in subsequent production of functional MMP2 and remodeling of collagen fibers. Thereby, matrix stiffness-induced activation of mechanotransduction signaling cascades leads to further ECM remodeling, potentiating the detrimental feed-forward loop (Barcus et al. 2013, Barcus et al. 2015, Barcus et al. 2016).
Influence of hormone signaling on angiogenesis
A key requirement of tumor growth is the generation and maintenance of vascular networks that allow nutrient supply as well as a means of tumor cell escape. The process of forming new vascular structures, termed angiogenesis, is coordinated by the release of pro-angiogenic factors from tumor cells and stromal cells that recruit and reorganize endothelial cells (Poltavets et al. 2018). It was reported that estrogen increases intra-tumoral vessel density and stabilizes tumor vasculature to prevent hypoxia and necrosis, via interaction with ER on stromal cells. This promoted the growth of ER– cancer cells, establishing that ER expression in the TME is necessary for generation of tumor vasculature including in the context of hormone receptor-negative breast cancers (Pequeux et al. 2012). Using human umbilical vein endothelial cells, it was demonstrated that estrogen directly induces the migration and proliferation of endothelial cells. Interestingly, estrogen also increased endothelial cell attachment to ECM proteins laminin, collagen, and fibronectin (Morales et al. 1995). Progesterone signaling also influences endothelial cells (Botelho et al. 2015), for example, pro-angiogenic THBS-1 produced by progesterone-treated breast cancer cells has been shown to stimulate endothelial cell proliferation (Hyder et al. 2009).
Cancer cells under hypoxia secrete vascular endothelial growth factor (VEGF), which engages VEGF receptor on endothelial cells to stimulate their proliferation, migration, and organization (De Palma et al. 2017). The VEGF gene contains functional EREs, suggesting that VEGF is a target gene of ER in breast cancer cells (Hyder et al. 2000, Applanat et al. 2008); however, the role of hormone signaling in VEGF production in breast cancer is somewhat controversial. Using ER+ MCF7 and androgen-regulated S115 breast cancer cell lines, it was shown that respective estrogen and testosterone treatment significantly increased VEGF mRNA and protein levels (Ruohola et al. 1999, Applanat et al. 2008). Hormone receptor-negative MDA-MB-231 cells co-transfected with ERα and ERβ, and therefore able to respond to estrogen, also have increased VEGF (Applanat et al. 2008). Furthermore, progesterone has been shown to promote angiogenesis via VEGF stimulation (Botelho et al. 2015). In contrast, it has been suggested that hormone-dependent regulation of VEGF expression seen in normal breast is lost during the progression of cancer (Greb et al. 1999) and that VEGF expression is predominantly induced by hypoxia and not overtly regulated by estrogen or progesterone (Scott et al. 1998).
In addition, it has been shown that pharmacological treatment with anti-estrogens acts agonistically to increase intracellular VEGF mRNA and protein (Ruohola et al. 1999, Bogin & Degani 2002). This conflicts with other studies reporting that treatment (including with clomiphene, tamoxifen, and nafoxidine) significantly inhibited angiogenesis, decreased levels of secreted VEGF as well as the angiogenic factor angiogenin, and increased the levels of the angiogenesis inhibitor endostatin (Gagliardi & Collins 1993, Garvin & Dabrosin 2003, Aberg et al. 2011). These contradictions may be due to model limitations (cell line dependent), and potential variations in hormone interactions with their receptors. For example, it was suggested that ERα and ERβ had different transactivation mechanisms in the presence of tamoxifen (Buteau-Lozano et al. 2002), that mutations in the BRCA1 gene could regulate ER-induced VEGF production (Kawai et al. 2002), and that ER signaling required cooperation with c-Myc for adequate VEGF expression (Dadiani et al. 2009). This highlights the need for development of models that better encompass both the tumor and components of its microenvironment to mimic in situ interactions.
In addition to cancer cell-mediated angiogenesis, stromal cells under the influence of hormone signaling (as canvassed above) significantly contribute to the formation of vascular networks. TAMs secrete pro-angiogenic factors (including VEGF, GLUT1, GLUT3, iNOS, TNF, interleukins, and chemokines) and Wnts, and tumor hypoxia exacerbates this pro-angiogenic function (Mazzieri et al. 2011, Van Overmeire et al. 2014, De Palma et al. 2017). CAFs are also a major source of VEGF, and in mammary tumors formed from ER+ cells, they recruit endothelial cells to vascularize the tumor and promote growth (Orimo et al. 2005). There have also been documented roles for a number of immune cell types in control of angiogenesis via secretion of pro-angiogenic factors and cytokines, modulation of myeloid cells, control of endothelial cell proliferation, and activation of macrophages (De Palma et al. 2017).
The presence of leaky blood vessels in the TME allows for interactions between tumor cells and platelets, which can be activated and release granular contents to promote tumor progression. When exposed to platelet-rich plasma, hormone-dependent ER+ breast cancer cells exhibit enhanced EMT, indicative of enhanced invasive phenotype (Augustine et al. 2020), and an increased platelet-to-lymphocyte ratio is associated with poorer outcome (Liu et al. 2016). Treatment of ER+ breast cancer cells with tamoxifen increases their ability to activate platelets (Pather et al. 2019), and in addition, tamoxifen has been shown to directly stimulate calcium influx in platelets, leading to their activation (Dobrydneva et al. 2007).
Conclusions
It has become increasingly evident that hormone receptor status and the pathways triggered by hormonal signaling can not only influence cancer cell proliferation and malignant properties but also the TME and tumor–TME cross-talk. In macrophages and fibroblasts, feed-forward mechanisms exist whereby hormone-stimulated cancer cells recruit and reprogram these stromal cell types to increase levels of estrogen in the tumor milieu and contribute to pathogenesis. Furthermore, these stromal cells increase their production and remodeling of the ECM, which cooperates with hormones to provide specific tumor-promoting mechanical signals to cancer cells. This is facilitated by hormone-influenced expression of integrins that detect changes in the ECM and enzymes such as MMPs that remodel the ECM. The hormonal status of tumors greatly influences the infiltrating immune cell profile, recruiting active populations of lymphocytes and others to shape the tumor landscape and contribute to immune escape, suppression of anti-tumor immunity, and anti-inflammatory phenotypic differentiation. In addition, the ability of tumors to generate and maintain functional vasculature is potentially dependent on signaling downstream of hormone receptor stimulation both in cancer cells and in stromal cells. Given the complex interactions between tumor and microenvironment, which are evidently strongly dictated by hormonal influence, future studies evaluating patient response to endocrine and immunotherapies in the context of the wider TME are warranted.
Declaration of interest
The author declares no competing interests.
Funding
S T B is supported by an Australian Research Council DECRA Fellowship.
Author contribution statement
S T B wrote the manuscript and performed the patient dataset analyses.
Acknowledgements
The author thanks Professor Michael Samuel for critical reading of the manuscript and their advice. Schematics were created with Biorender.com.
References
Aberg UW, Saarinen N, Abrahamsson A, Nurmi T, Engblom S & Dabrosin C 2011 Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLoS One 6 e25720. (https://doi.org/10.1371/journal.pone.0025720)
Adam L, Crepin M, Lelong JC, Spanakis E & Israel L 1994 Selective interactions between mammary epithelial cells and fibroblasts in co-culture. International Journal of Cancer 59 262–268. (https://doi.org/10.1002/ijc.2910590219)
Alcaraz J, Xu R, Mori H, Nelson CM, Mroue R, Spencer VA, Brownfield D, Radisky DC, Bustamante C & Bissell MJ 2008 Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO Journal 27 2829–2838. (https://doi.org/10.1038/emboj.2008.206)
Applanat MP, Buteau-Lozano H, Herve MA & Corpet A 2008 Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression. Advances in Experimental Medicine and Biology 617 437–444. (https://doi.org/10.1007/978-0-387-69080-3_42)
Arruvito L, Sanz M, Banham AH & Fainboim L 2007 Expansion of CD4+CD25+and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. Journal of Immunology 178 2572–2578. (https://doi.org/10.4049/jimmunol.178.4.2572)
Augustine TN, Pather K, Mak D, Klonaros D, Xulu K, Dix-Peek T, Duarte R & Van Der Spuy WJ 2020 Ex vivo interaction between blood components and hormone-dependent breast cancer cells induces alterations associated with epithelial-mesenchymal transition and thrombosis. Ultrastructural Pathology 44 262–272. (https://doi.org/10.1080/01913123.2020.1749197)
Azam S, Jacobsen KK, Aro AR, Lynge E & Andersen ZJ 2020 Hormone replacement therapy and mammographic density: a systematic literature review. Breast Cancer Research and Treatment 182 555–579. (https://doi.org/10.1007/s10549-020-05744-w)
Baral E, Nagy E, Kangas L & Berczi I 1997 Combination therapy of the H2712 murine mammary carcinoma with cytotoxic T lymphocytes and anti-estrogens. Anticancer Research 17 3647–3651. (https://doi.org/10.1158/1535-7163.MCT-19-0495)
Barcus CE, Holt EC, Keely PJ, Eliceiri KW & Schuler LA 2015 Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells. PLoS One 10 e0116891. (https://doi.org/10.1371/journal.pone.0116891)
Barcus CE, Keely PJ, Eliceiri KW & Schuler LA 2013 Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. Journal of Biological Chemistry 288 12722–12732. (https://doi.org/10.1074/jbc.M112.447631)
Barcus CE, Keely PJ, Eliceiri KW & Schuler LA 2016 Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells. Oncotarget 7 48093–48106. (https://doi.org/10.18632/oncotarget.10137)
Bogin L & Degani H 2002 Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Research 62 1948–1951.
Botelho MC, Soares R & Alves H 2015 Progesterone in breast cancer angiogenesis. SM Journal of Reproductive Health and Infertility 1 1001.
Boyd NF 2013 Mammographic density and risk of breast cancer. American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting 33 e57–e62. (https://doi.org/10.14694/EdBook_AM.2013.33.e57)
Boyle ST, Johan MZ & Samuel MS 2020a Tumour-directed microenvironment remodelling at a glance. Journal of Cell Science 133. (https://doi.org/10.1242/jcs.247783)
Boyle ST, Poltavets V, Kular J, Pyne NT, Sandow JJ, Lewis AC, Murphy KJ, Kolesnikoff N, Moretti PAB & Tea MN et al.2020b ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism. Nature Cell Biology 22 882–895. (https://doi.org/10.1038/s41556-020-0523-y)
Brechbuhl HM, Barrett AS, Kopin E, Hagen JC, Han AL, Gillen AE, Finlay-Schultz J, Cittelly DM, Owens P & Horwitz KB et al.2020 Fibroblast subtypes define a metastatic matrisome in breast cancer. JCI Insight 5. (https://doi.org/10.1172/jci.insight.130751)
Buteau-Lozano H, Ancelin M, Lardeux B, Milanini J & Perrot-Applanat M 2002 Transcriptional regulation of vascular endothelial growth factor by estradiol and tamoxifen in breast cancer cells: a complex interplay between estrogen receptors alpha and beta. Cancer Research 62 4977–4984.
Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y & Malaka DO et al.2011 Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Research and Treatment 128 703–711. (https://doi.org/10.1007/s10549-010-1154-y)
C ancer Genome Atlas 2012. Comprehensive molecular portraits of human breast tumours. Nature 490 61–70. (https://doi.org/10.1038/nature11412)
Cao H, Huang Y, Wang L, Wang H, Pang X, Li K, Dang W, Tang H, Wei L & Su M et al.2016 Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages. Oncotarget 7 65441–65453. (https://doi.org/10.18632/oncotarget.11761)
Chen L, Linden HM, Anderson Bo & Li CI 2014 Trends in 5-year survival rates among breast cancer patients by hormone receptor status and stage. Breast Cancer Research and Treatment 147 609–616. (https://doi.org/10.1007/s10549-014-3112-6)
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J & Sarto GE et al.2010 Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304 1684–1692. (https://doi.org/10.1001/jama.2010.1500)
Chottanapund S, Van Duursen MB, Navasumrit P, Hunsonti P, Timtavorn S, Ruchirawat M & Van Den Berg M 2013 Effect of androgens on different breast cancer cells co-cultured with or without breast adipose fibroblasts. Journal of Steroid Biochemistry and Molecular Biology 138 54–62. (https://doi.org/10.1016/j.jsbmb.2013.03.007)
Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, Friedl A & Keely PJ 2011 Aligned collagen is a prognostic signature for survival in human breast carcinoma. American Journal of Pathology 178 1221–1232. (https://doi.org/10.1016/j.ajpath.2010.11.076)
Cunha GR, Young P, Hom YK, Cooke PS, Taylor JA & Lubahn DB 1997 Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. Journal of Mammary Gland Biology and Neoplasia 2 393–402. (https://doi.org/10.1023/a:1026303630843)
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S & Yuan Y et al.2012 The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486 346–352. (https://doi.org/10.1038/nature10983)
Dadiani M, Seger D, Kreizman T, Badikhi D, Margalit R, Eilam R & Degani H 2009 Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor alpha and c-Myc. Endocrine-Related Cancer 16 819–834. (https://doi.org/10.1677/ERC-08-0249)
Dannenfelser R, Nome M, Tahiri A, Ursini-Siegel J, Vollan HKM, Haakensen VD, Helland Å, Naume B, Caldas C & Børresen-Dale AL et al.2017 Data-driven analysis of immune infiltrate in a large cohort of breast cancer and its association with disease progression, ER activity, and genomic complexity. Oncotarget 8 57121–57133. (https://doi.org/10.18632/oncotarget.19078)
De Palma M, Biziato D & Petrova TV 2017 Microenvironmental regulation of tumour angiogenesis. Nature Reviews. Cancer 17 457–474. (https://doi.org/10.1038/nrc.2017.51)
Deak SB, Glaug MR, Pierce RA, Bancila E, Amenta P, Mackenzie JW, Greco RS & Boyd CD 1991 Desmoplasia in benign and malignant breast disease is characterized by alterations in level of mRNAs coding for types I and III procollagen. Matrix 11 252–258. (https://doi.org/10.1016/s0934-8832(1180232-5)
Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R & Hanusch C et al.2010 Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. Journal of Clinical Oncology 28 105–113. (https://doi.org/10.1200/JCO.2009.23.7370)
Denkert C, Von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F & Furlanetto J et al.2018 Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet. Oncology 19 40–50. (https://doi.org/10.1016/S1470-2045(1730904-X)
Desmedt C, Salgado R, Fornili M, Pruneri G, Van Den Eynden G, Zoppoli G, Rothe F, Buisseret L, Garaud S & Willard-Gallo K et al.2018 Immune infiltration in invasive lobular breast cancer. Journal of the National Cancer Institute 110 768–776. (https://doi.org/10.1093/jnci/djx268)
Dittmer A, Lange T, Leyh B & Dittmer J 2020 Protein and growth-modulatory effects of carcinoma-associated fibroblasts on breast cancer cells: role of interleukin-6. International Journal of Oncology 56 258–272. (https://doi.org/10.3892/ijo.2019.4918)
Dobrydneva Y, Weatherman RV, Trebley JP, Morrell MM, Fitzgerald MC, Fichandler CE, Chatterjie N & Blackmore PF 2007 Tamoxifen stimulates calcium entry into human platelets. Journal of Cardiovascular Pharmacology 50 380–390. (https://doi.org/10.1097/FJC.0b013e31811ec748)
Faas M, Bouman A, Moesa H, Heineman MJ, De Leij L & Schuiling G 2000 The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertility and Sterility 74 1008–1013. (https://doi.org/10.1016/s0015-0282(0001553-3)
Fischer C, Mamillapalli R, Goetz LG, Jorgenson E, Ilagan Y & Taylor HS 2016 Bisphenol A (BPA) exposure in utero leads to immunoregulatory cytokine dysregulation in the mouse mammary gland: a potential mechanism programming breast cancer risk. Hormones and Cancer 7 241–251. (https://doi.org/10.1007/s12672-016-0254-5)
Fleming JM, Miller TC, Kidacki M, Ginsburg E, Stuelten CH, Stewart DA, Troester MA & Vonderhaar BK 2012 Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo. Breast Cancer Research 14 R97. (https://doi.org/10.1186/bcr3215)
Gagliardi A & Collins DC 1993 Inhibition of angiogenesis by antiestrogens. Cancer Research 53 533–535.
Garaud S, Buisseret L, Solinas C, Gu-Trantien C, De Wind A, Van Den Eynden G, Naveaux C, Lodewyckx JN, Boisson A & Duvillier H et al.2019 Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight 5. (https://doi.org/10.1172/jci.insight.129641)
Garvin S & Dabrosin C 2003 Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Research 63 8742–8748.
Gelsomino L, Giordano C, Camera G, Sisci D, Marsico S, Campana A, Tarallo R, Rinaldi A, Fuqua S & Leggio A et al.2020 Leptin signaling contributes to aromatase inhibitor resistant breast cancer cell growth and activation of macrophages. Biomolecules 10. (https://doi.org/10.3390/biom10040543)
Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M & Aguggini S et al.2009 Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clinical Cancer Research 15 1046–1051. (https://doi.org/10.1158/1078-0432.CCR-08-1507)
Glajcar A, Szpor J, Hodorowicz-Zaniewska D, Tyrak KE & Okon K 2019 The composition of T cell infiltrates varies in primary invasive breast cancer of different molecular subtypes as well as according to tumor size and nodal status. Virchows Archiv 475 13–23. (https://doi.org/10.1007/s00428-019-02568-y)
Goldberg J, Pastorello RG, Vallius T, Davis J, Cui YX, Agudo J, Waks AG, Keenan T, Mcallister SS & Tolaney SM et al.2021 The immunology of hormone receptor positive breast cancer. Frontiers in Immunology 12 674192. (https://doi.org/10.3389/fimmu.2021.674192)
Greb RR, Maier I, Wallwiener D & Kiesel L 1999 Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions. British Journal of Cancer 81 225–231. (https://doi.org/10.1038/sj.bjc.6690681)
Guo Q, Sun D, Barrett AS, Jindal S, Pennock ND, Conklin MW, Xia Z, Mitchell E, Samatham R & Mirza N et al.2022 Mammary collagen is under reproductive control with implications for breast cancer. Matrix Biology 105 104–126. (https://doi.org/10.1016/j.matbio.2021.10.006)
Gwak JM, Jang MH, Kim DI, Seo AN & Park SY 2015 Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One 10 e0125728. (https://doi.org/10.1371/journal.pone.0125728)
Hansen RK & Bissell MJ 2000 Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones. Endocrine-Related Cancer 7 95–113. (https://doi.org/10.1677/erc.0.0070095)
Haslam SZ & Woodward TL 2003 Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Research 5 208–215. (https://doi.org/10.1186/bcr615)
Hazlett J, Niemi V, Aiderus A, Powell K, Wise L, Kemp R & Dunbier AK 2021 Oestrogen deprivation induces chemokine production and immune cell recruitment in in vitro and in vivo models of oestrogen receptor-positive breast cancer. Breast Cancer Research 23 95. (https://doi.org/10.1186/s13058-021-01472-1)
Hollmen M, Roudnicky F, Karaman S & Detmar M 2015 Characterization of macrophage--cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Scientific Reports 5 9188. (https://doi.org/10.1038/srep09188)
Hyder SM, Liang Y, Wu J & Welbern V 2009 Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells. Endocrine-Related Cancer 16 809–817. (https://doi.org/10.1677/ERC-08-0311)
Hyder SM, Nawaz Z, Chiappetta C & Stancel GM 2000 Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Research 60 3183–3190.
Ingman WV, Wyckoff J, Gouon-Evans V, Condeelis J & Pollard JW 2006 Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Developmental Dynamics 235 3222–3229. (https://doi.org/10.1002/dvdy.20972)
Isfoss BL, Holmqvist B, Sand E, Forsell J, Jernstrom H & Olsson H 2018 Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer - an observational study. BMC Cancer 18 230. (https://doi.org/10.1186/s12885-018-4151-x)
Jallow F, O'Leary KA, Rugowski DE, Guerrero JF, Ponik SM & Schuler LA 2019 Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer. Oncogene 38 6913–6925. (https://doi.org/10.1038/s41388-019-0941-0)
Jiang X, Orr BA, Kranz DM & Shapiro DJ 2006 Estrogen induction of the granzyme B inhibitor, proteinase inhibitor 9, protects cells against apoptosis mediated by cytotoxic T lymphocytes and natural killer cells. Endocrinology 147 1419–1426. (https://doi.org/10.1210/en.2005-0996)
Katsuta E, Yan L, Opyrchal M, Kalinski P & Takabe K 2021 Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer. Therapeutic Advances in Medical Oncology 13 17588359211006680. (https://doi.org/10.1177/17588359211006680)
Kauppila S, Stenback F, Risteli J, Jukkola A & Risteli L 1998 Aberrant type I and type III collagen gene expression in human breast cancer in vivo. Journal of Pathology 186 262–268. (https://doi.org/10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3)
Kawai H, Li H, Chun P, Avraham S & Avraham HK 2002 Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene 21 7730–7739. (https://doi.org/10.1038/sj.onc.1205971)
Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO & Gelmon K 2010 Metastatic behavior of breast cancer subtypes. Journal of Clinical Oncology 28 3271–3277. (https://doi.org/10.1200/JCO.2009.25.9820)
Knower KC, Chand AL, Eriksson N, Takagi K, Miki Y, Sasano H, Visvader JE, Lindeman GJ, Funder JW & Fuller PJ et al.2013 Distinct nuclear receptor expression in stroma adjacent to breast tumors. Breast Cancer Research and Treatment 142 211–223. (https://doi.org/10.1007/s10549-013-2716-6)
Kolesnikoff N, Chen CH & Samuel MS 2022 Interrelationships between the extracellular matrix and the immune microenvironment that govern epithelial tumour progression. Clinical Science 136 361–377. (https://doi.org/10.1042/CS20210679)
Lee JH, Lydon JP & Kim CH 2012 Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. European Journal of Immunology 42 2683–2696. (https://doi.org/10.1002/eji.201142317)
Lelu K, Laffont S, Delpy L, Paulet PE, Perinat T, Tschanz SA, Pelletier L, Engelhardt B & Guery JC 2011 Estrogen receptor alpha signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. Journal of Immunology 187 2386–2393. (https://doi.org/10.4049/jimmunol.1101578)
Leyh B, Dittmer A, Lange T, Martens JW & Dittmer J 2015 Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis. Oncotarget 6 39307–39328. (https://doi.org/10.18632/oncotarget.5624)
Li CI, Malone KE, Porter PL, Lawton TJ, Voigt LF, Cushing-Haugen KL, Lin MG, Yuan X & Daling JR 2008 Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiology, Biomarkers and Prevention 17 43–50. (https://doi.org/10.1158/1055-9965.EPI-07-0558)
Li D, Ji H, Niu X, Yin L, Wang Y, Gu Y, Wang J, Zhou X, Zhang H & Zhang Q 2020 Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer. Cancer Science 111 47–58. (https://doi.org/10.1111/cas.14230)
Li K, Wei L, Huang Y, Wu Y, Su M, Pang X, Wang N, Ji F, Zhong C & Chen T 2016 Leptin promotes breast cancer cell migration and invasion via IL-18 expression and secretion. International Journal of Oncology 48 2479–2487. (https://doi.org/10.3892/ijo.2016.3483)
Liu C, Huang Z, Wang Q, Sun B, Ding L, Meng X & Wu S 2016 Usefulness of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in hormone-receptor-negative breast cancer. OncoTargets and Therapy 9 4653–4660. (https://doi.org/10.2147/OTT.S106017)
Liu J, Shen JX, Wu HT, Li XL, Wen XF, Du CW & Zhang GJ 2018 Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discovery Medicine 25 211–223.
Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z & Nielsen TO 2014 Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Research 16 432. (https://doi.org/10.1186/s13058-014-0432-8)
Loibl S, Poortmans P, Morrow M, Denkert C & Curigliano G 2021 Breast cancer. Lancet 397 1750–1769. (https://doi.org/10.1016/S0140-6736(2032381-3)
Lopes-Coelho F, Andre S, Felix A & Serpa J 2018 Breast cancer metabolic cross-talk: fibroblasts are hubs and breast cancer cells are gatherers of lipids. Molecular and Cellular Endocrinology 462 93–106. (https://doi.org/10.1016/j.mce.2017.01.031)
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO & Green AR 2011 An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Research and Treatment 127 99–108. (https://doi.org/10.1007/s10549-010-0987-8)
Mak KM, Png CY & Lee DJ 2016 Type V collagen in health, disease, and fibrosis. Anatomical Record 299 613–629. (https://doi.org/10.1002/ar.23330)
Marbaix E, Donnez J, Courtoy PJ & Eeckhout Y 1992 Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants. PNAS 89 11789–11793. (https://doi.org/10.1073/pnas.89.24.11789)
Margolis RN, Evans RM, O'Malley BW & NURSA Atlas Consortium 2005 The Nuclear Receptor Signaling Atlas: development of a functional atlas of nuclear receptors. Molecular Endocrinology 19 2433–2436. (https://doi.org/10.1210/me.2004-0461)
Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi Ls, Gentner B, Brown JL & Naldini L et al.2011 Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19 512–526. (https://doi.org/10.1016/j.ccr.2011.02.005)
Meng L, Zhou J, Sasano H, Suzuki T, Zeitoun KM & Bulun SE 2001 Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction. Cancer Research 61 2250–2255.
Mor G, Yue W, Santen RJ, Gutierrez L, Eliza M, Berstein Lm, Harada N, Wang J, Lysiak J & Diano S et al.1998 Macrophages, estrogen and the microenvironment of breast cancer. Journal of Steroid Biochemistry and Molecular Biology 67 403–411. (https://doi.org/10.1016/s0960-0760(9800143-5)
Morales DE, Mcgowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK & Schnaper HW 1995 Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91 755–763. (https://doi.org/10.1161/01.cir.91.3.755)
Need EF, Atashgaran V, Ingman WV & Dasari P 2014 Hormonal regulation of the immune microenvironment in the mammary gland. Journal of Mammary Gland Biology and Neoplasia 19 229–239. (https://doi.org/10.1007/s10911-014-9324-x)
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL & Weinberg RA 2005 Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121 335–348. (https://doi.org/10.1016/j.cell.2005.02.034)
Pather K, Dix-Peek T, Duarte R, Chetty N & Augustine TN 2019 Breast cancer cell-induced platelet activation is compounded by tamoxifen and anastrozole in vitro. Thrombosis Research 177 51–58. (https://doi.org/10.1016/j.thromres.2019.02.027)
Paulose T, Speroni L, Sonnenschein C & Soto AM 2015 Estrogens in the wrong place at the wrong time: fetal BPA exposure and mammary cancer. Reproductive Toxicology 54 58–65. (https://doi.org/10.1016/j.reprotox.2014.09.012)
Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I, Costa A, Givel AM, Attieh Y & Barbazan J et al.2020 Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nature Communications 11 404. (https://doi.org/10.1038/s41467-019-14134-w)
Pequeux C, Raymond-Letron I, Blacher S, Boudou F, Adlanmerini M, Fouque MJ, Rochaix P, Noel A, Foidart JM & Krust A et al.2012 Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis. Cancer Research 72 3010–3019. (https://doi.org/10.1158/0008-5472.CAN-11-3768)
Perou CM, Sorlie T, Eisen MB, Van De Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H & Akslen LA et al.2000 Molecular portraits of human breast tumours. Nature 406 747–752. (https://doi.org/10.1038/35021093)
Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF & Offner H 2004 Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. Journal of Immunology 173 2227–2230. (https://doi.org/10.4049/jimmunol.173.4.2227)
Polanczyk MJ, Hopke C, Vandenbark AA & Offner H 2007 Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). International Immunology 19 337–343. (https://doi.org/10.1093/intimm/dxl151)
Poltavets V, Kochetkova M, Pitson SM & Samuel MS 2018 The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Frontiers in Oncology 8 431. (https://doi.org/10.3389/fonc.2018.00431)
Pontiggia O, Sampayo R, Raffo D, Motter A, Xu R, Bissell MJ, Joffe EB & Simian M 2012 The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through beta1 integrin. Breast Cancer Research and Treatment 133 459–471. (https://doi.org/10.1007/s10549-011-1766-x)
Prieto GA & Rosenstein Y 2006 Oestradiol potentiates the suppressive function of human CD4+ CD25+ regulatory T cells by promoting their proliferation. Immunology 118 58–65. (https://doi.org/10.1111/j.1365-2567.2006.02339.x)
Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG & Keely PJ 2006 Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine 4 38. (https://doi.org/10.1186/1741-7015-4-38)
Pyla RD, Potekar RM, Patil VS, Reddy AK & Sathyashree KV 2020 Quantitative mast cell analysis and hormone receptor study (ER, PR and HER2/neu) in invasive carcinoma of breast. Indian Journal of Pathology and Microbiology 63 200–204. (https://doi.org/10.4103/IJPM.IJPM_155_19)
Qian F, Qingping Y, Linquan W, Xiaojin H, Rongshou W, Shanshan R, Wenjun L, Yong H & Enliang L 2017 High tumor-infiltrating FoxP3(+) T cells predict poor survival in estrogen receptor-positive breast cancer: a meta-analysis. European Journal of Surgical Oncology 43 1258–1264. (https://doi.org/10.1016/j.ejso.2017.01.011)
Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ, Robertson JF, Blamey R, Gee J & Nicholson RI et al.2008 Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. European Journal of Cancer 44 73–83. (https://doi.org/10.1016/j.ejca.2007.10.009)
Ren W, Zhang Y, Zhang L, Lin Q, Zhang J & Xu G 2018 Overexpression of collagen type V alpha1 chain in human breast invasive ductal carcinoma is mediated by TGF-beta1. International Journal of Oncology 52 1694–1704. (https://doi.org/10.3892/ijo.2018.4317)
Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C & Kulkarni P et al.2007 Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9 166–180. (https://doi.org/10.1593/neo.07112)
Rothenberger NJ, Somasundaram A & Stabile LP 2018 The role of the estrogen pathway in the tumor microenvironment. International Journal of Molecular Sciences 19 611. (https://doi.org/10.3390/ijms19020611)
Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K & Harkonen PL 1999 Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Molecular and Cellular Endocrinology 149 29–40. (https://doi.org/10.1016/s0303-7207(9900003-9)
Santen RJ, Santner SJ, Pauley RJ, Tait L, Kaseta J, Demers LM, Hamilton C, Yue W & Wang JP 1997 Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible? Journal of Steroid Biochemistry and Molecular Biology 61 267–271. (https://doi.org/10.1016/S0960-0760(9780022-2)
Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, Salgado R, Byrne Dj, Teo ZL & Dushyanthen S et al.2018. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nature Medicine 24 986–993. (https://doi.org/10.1038/s41591-018-0078-7)
Scott PA, Gleadle JM, Bicknell R & Harris AL 1998 Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. International Journal of Cancer 75 706–712. (https://doi.org/10.1002/(sici)1097-0215(19980302)75:5<706::aid-ijc8>3.0.co;2-2)
Segovia-Mendoza M & Morales-Montor J 2019 Immune tumor microenvironment in breast cancer and the participation of estrogen and its receptors in cancer physiopathology. Frontiers in Immunology 10 348. (https://doi.org/10.3389/fimmu.2019.00348)
Shah SH, Miller P, Garcia-Contreras M, Ao Z, Machlin L, Issa E & El-Ashry D 2015 Hierarchical paracrine interaction of breast cancer associated fibroblasts with cancer cells via hMAPK-microRNAs to drive ER-negative breast cancer phenotype. Cancer Biology and Therapy 16 1671–1681. (https://doi.org/10.1080/15384047.2015.1071742)
Simian M, Bissell MJ, Barcellos-Hoff MH & Shyamala G 2009 Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice. Breast Cancer Research 11 R72. (https://doi.org/10.1186/bcr2408)
Skandalis SS, Afratis N, Smirlaki G, Nikitovic D, Theocharis AD, Tzanakakis GN & Karamanos NK 2014 Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans. Matrix Biology 35 182–193. (https://doi.org/10.1016/j.matbio.2013.09.002)
Somasundaram A, Rothenberger NJ & Stabile LP 2020 The impact of estrogen in the tumor microenvironment. Advances in Experimental Medicine and Biology 1277 33–52. (https://doi.org/10.1007/978-3-030-50224-9_2)
Song K, Yu Z, Zu X, Li G, Hu Z & Xue Y 2022 Collagen remodeling along cancer progression providing a novel opportunity for cancer diagnosis and treatment. International Journal of Molecular Sciences 23 10509. (https://doi.org/10.3390/ijms231810509)
Stanton SE & Disis ML 2016 Clinical significance of tumor-infiltrating lymphocytes in breast cancer. Journal for ImmunoTherapy of Cancer 4 59. (https://doi.org/10.1186/s40425-016-0165-6)
Studebaker AW, Storci G, Werbeck JL, Sansone P, Sasser AK, Tavolari S, Huang T, Chan MW, Marini FC & Rosol TJ et al.2008 Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Research 68 9087–9095. (https://doi.org/10.1158/0008-5472.CAN-08-0400)
Svensson S, Abrahamsson A, Rodriguez GV, Olsson AK, Jensen L, Cao Y & Dabrosin C 2015 CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clinical Cancer Research 21 3794–3805. (https://doi.org/10.1158/1078-0432.CCR-15-0204)
Takada K, Kashiwagi S, Asano Y, Goto W, Takahashi K, Shibutani M, Amano R, Takashima T, Tomita S & Hirakawa K et al.2019 Clinical evaluation of dynamic monitoring of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in primary endocrine therapy for advanced breast cancer. Anticancer Research 39 5581–5588. (https://doi.org/10.21873/anticanres.13752)
Valdes-Mora F, Salomon R, Gloss BS, Law AMK, Venhuizen J, Castillo L, Murphy KJ, Magenau A, Papanicolaou M & Rodriguez De La Fuente L et al.2021 Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype. Cell Reports 35 108945. (https://doi.org/10.1016/j.celrep.2021.108945)
Van Overmeire E, Laoui D, Keirsse J & Van Ginderachter JA 2014 Hypoxia and tumor-associated macrophages: a deadly alliance in support of tumor progression. Oncoimmunology 3 e27561. (https://doi.org/10.4161/onci.27561)
Vincent AJ & Salamonsen LA 2000 The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives. Human Reproduction 15(Supplement 3) 135–143. (https://doi.org/10.1093/humrep/15.suppl_3.135)
Wadia PR, Cabaton NJ, Borrero MD, Rubin BS, Sonnenschein C, Shioda T & Soto AM 2013 Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland. PLoS One 8 e63902. (https://doi.org/10.1371/journal.pone.0063902)
Waks AG, Stover DG, Guerriero JL, Dillon D, Barry WT, Gjini E, Hartl C, Lo W, Savoie J & Brock J et al.2019 The immune microenvironment in hormone receptor-positive breast cancer before and after preoperative chemotherapy. Clinical Cancer Research 25 4644–4655. (https://doi.org/10.1158/1078-0432.CCR-19-0173)
Wang X, Docanto MM, Sasano H, Lo C, Simpson ER, Brown KA & Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer 2015 Prostaglandin E2 inhibits p53 in human breast adipose stromal cells: a novel mechanism for the regulation of aromatase in obesity and breast cancer. Cancer Research 75 64 5–655.
Williams MM, Spoelstra NS, Arnesen S, O'Neill KI, Christenson JL, Reese J, Torkko KC, Goodspeed A, Rosas E & Hanamura T et al.2021 Steroid hormone receptor and infiltrating immune cell status reveals therapeutic vulnerabilities of ESR1-mutant breast cancer. Cancer Research 81 732–746. (https://doi.org/10.1158/0008-5472.CAN-20-1200)
Woodward TL, Lu H & Haslam SZ 2000 Laminin inhibits estrogen action in human breast cancer cells. Endocrinology 141 2814–2821. (https://doi.org/10.1210/endo.141.8.7607)
Woodward TL, Mienaltowski AS, Modi RR, Bennett JM & Haslam SZ 2001 Fibronectin and the alpha(5)beta(1) integrin are under developmental and ovarian steroid regulation in the normal mouse mammary gland. Endocrinology 142 3214–3222. (https://doi.org/10.1210/endo.142.7.8273)
Xu R, Nelson CM, Muschler JL, Veiseh M, Vonderhaar BK & Bissell MJ 2009 Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function. Journal of Cell Biology 184 57–66. (https://doi.org/10.1083/jcb.200807021)
Xuan QJ, Wang JX, Nanding A, Wang ZP, Liu H, Lian X & Zhang QY 2014 Tumor-associated macrophages are correlated with tamoxifen resistance in the postmenopausal breast cancer patients. Pathology Oncology Research 20 619–624. (https://doi.org/10.1007/s12253-013-9740-z)
Yamaguchi M, Takagi K, Sato M, Sato A, Miki Y, Onodera Y, Miyashita M, Sasano H & Suzuki T 2021 Androgens enhance the ability of intratumoral macrophages to promote breast cancer progression. Oncology Reports 46 188. (https://doi.org/10.3892/or.2021.8139)
Yamaguchi Y 2007 Microenvironmental regulation of estrogen signals in breast cancer. Breast Cancer (Tokyo, Japan) 14 175–181. (https://doi.org/10.2325/jbcs.975)
Yamaguchi Y, Takei H, Suemasu K, Kobayashi Y, Kurosumi M, Harada N & Hayashi S 2005 Tumor-stromal interaction through the estrogen-signaling pathway in human breast cancer. Cancer Research 65 4653–4662. (https://doi.org/10.1158/0008-5472.CAN-04-3236)
Zhou J, Gurates B, Yang S, Sebastian S & Bulun SE 2001 Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta. Cancer Research 61 2328–2334.
