Introduction Aromatase inhibitors (AIs) are commonly used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. Although AIs are generally well tolerated with few serious adverse events, a number of
M Rodríguez-Sanz, N García-Giralt, D Prieto-Alhambra, S Servitja, S Balcells, R Pecorelli, A Díez-Pérez, D Grinberg, I Tusquets and X Nogués
C Roger, S Lambard, A Bouskine, B Mograbi, D Chevallier, M Nebout, G Pointis, S Carreau and P Fenichel
(see review in Jones & Simpson 2000 ). Indeed, estrogen is found at a higher level in mature testis than in circulating plasma in relation to its production through testosterone conversion by aromatase complex ( Carreau et al. 2002 ). Of particular
Dorothée Silandre, Christelle Delalande, Philippe Durand and Serge Carreau
related to aromatase activity. Aromatase, an enzymatic complex, catalyzes conversion of androgens into estrogens and is localized in the endoplasmic reticulum of various tissues including brain, gonads, placenta, and adipose tissue. Aromatase is composed
Edward F Orlando, Yoshinao Katsu, Shinichi Miyagawa and Taisen Iguchi
, Devlin & Nagahama 2002 ). The importance of the relative concentration of these sex steroids has been documented by the manipulation of aromatase, the enzyme that converts androgens to estrogens. Inhibition or stimulation of aromatase can reverse sex as
Maëlle Pannetier, Stéphane Fabre, Frank Batista, Ayhan Kocer, Lauriane Renault, Geneviève Jolivet, Béatrice Mandon-Pépin, Corinne Cotinot, Reiner Veitia and Eric Pailhoux
), the spatio-temporal expression profile of FOXL2 is strongly correlated with those of the CYP19 gene encoding aromatase, an enzyme responsible for the conversion of androgens into estrogens (for review see Conley & Hinshelwood 2001 ). Then, one
OK Oz, R Millsaps, R Welch, J Birch and JE Zerwekh
Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.
Y Kazeto and J M Trant
). Therefore, the precise regulation of E 2 biosynthesis, controlled primarily through the expression of genes encoding steroidogenic enzymes, is apparently required for reproductive success. Cytochrome P450 aromatase (CYP19) is the terminal steroidogenic
P Sourdaine, M G Parker, J Telford and W R Miller
Aromatase activity may be detected in most, but not all, breast cancers, and in certain tumours there appears to be decreased sensitivity to the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA). The aims of the present study were to measure aromatase activity, and its sensitivity to 4-OHA, in breast tumours, and to examine the CYP19 gene encoding the aromatase cytochrome P450 (P450arom) for the presence of mutations.
In vitro aromatase activity and sensitivity to 4-OHA were measured by determining the conversion of tritiated testosterone to tritiated oestradiol in breast tumour tissue in the absence and presence of 4-OHA (10 nm). Genomic DNA was extracted from five tumours: one showing no detectable aromatase activity and four displaying evidence of aromatase activity (two sensitive and two insensitive to 4-OHA). Subsequent PCR-single-strand conformation polymorphism analysis revealed a variation in the mobility of single-stranded DNA for exons III, VII and X, corresponding, as shown by direct sequencing of PCR products, to common polymorphism of the aromatase gene. This study does not provide evidence for mutation in the coding exons of the P450arom gene which would account for either the absence of aromatase activity or its changed sensitivity to 4-OHA in breast cancers.
M Watanabe, ER Simpson, N Pathirage, S Nakajin and CD Clyne
A number of clinical studies have highlighted the importance of estrogen in bone growth and maintenance in men and postmenopausal women. In these instances, estrogen is synthesized locally within bone tissue by aromatase, encoded by the CYP19 gene. The mechanisms regulating aromatase expression in bone, however, are unclear. In this work we characterized the expression of aromatase activity and gene transcripts in the human fetal osteoblastic cell line, SV-HFO. Aromatase activity and gene transcript expression were stimulated by dexamethasone. Oncostatin M strongly stimulated aromatase expression in synergy with dexamethasone. These factors induced CYP19 transcripts that included the sequence of exon I.4 in their 5'UTR. Consistent with this, a reporter construct harboring the genomic sequence of the promoter region of exon I.4 (promoter I.4) was also activated by dexamethasone and oncostatin M. 5' deletion and mutation analysis revealed important roles for a glucocorticoid response element, an interferon gamma activating sequence and a putative binding site for Sp1. Transfection of exogenous glucocorticoid receptor, STAT3 or Sp1 increased promoter activity, indicating a potential role for these transcription factors in regulating aromatase expression in SV-HFO cells. These data suggest that the SV-HFO cell line is a valuable model with which to elucidate the mechanisms regulating local estrogen synthesis in osteoblasts.
S Bourguiba, S Lambard and S Carreau
The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase. In rodents, germ cell production of estrogens is known, although the regulation of the cytochrome p450 aromatase (p450 arom) gene expression is not completely elucidated. In the present study, we have investigated the putative effects of steroids (testosterone, 5alpha-dihydrotestosterone (DHT) and estradiol) on Cyp19 gene expression in purified adult rat pachytene spermatocytes (PSs) and round spermatids (RSs). Using a highly specific quantitative competitive RT-PCR method we established that testosterone enhances in a dose- and time-related manner aromatase gene expression in PSs and RSs; 5alpha-DHT induces the same effect. Furthermore, testosterone increases the estradiol output in both germ cell populations whereas 5alpha-DHT was inefficient, therefore suggesting that the effect of androgens on p450 arom gene transcription was independent of estrogen formation. In fact estradiol inhibits the Cyp19 gene expression in PSs and RSs. ICI 182780, an estrogen receptor antagonist, has no effect on testosterone-stimulated aromatase expression in PSs and RSs. By contrast, ICI 182780 suppresses the inhibitory effect of estradiol on p450 arom mRNA expression in PSs and RSs. Similarly, nilutamide, a non-steroidal anti-androgen specific for androgen receptors, abolishes the testosterone-stimulated aromatase expression in PSs and RSs. These observations show that androgens up-regulate aromatase gene expression in purified adult rat germ cells whereas estrogens exert an opposite effect, which may suggest the presence of androgen and estrogen responsive elements on the aromatase promoter(s).