The effect of adipocyte-macrophage cross-talk in obesity-related breast cancer

in Journal of Molecular Endocrinology
Correspondence: Ayse Basak Engin, Email: abengin@gmail.com
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Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid- and tumor necrosis factor-α involving vicious cycle between adipocytes and macrophages aggravates inflammatory changes. Thereby, M1 macrophages form a characteristic "crown-like structures (CLSs)" around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity, and aggressive behavior of breast cancer cells. Inter-linked molecular mechanisms between adipocyte-macrophage-breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1-TSC2 complex-mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R) positive postmenopausal breast cancer growth in obesity, adipocyte-macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin, insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin-estrogen-macrophage axis, and sirtuin 1 (SIRT1)-adipose resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

 

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