The ovarian production of steroid hormones throughout a woman’s lifetime is ample and varied, with important changes during different life stages. Estrogens are the most prominent ovarian hormones in terms of their morphogenetic and mitogenic capabilities, but they are secreted in low quantities.

Progestagens (progesterone and 16α -OH progesterone) are the steroid hormones most secreted by the ovaries during the fertile period of a woman’s life. Androgens (androstenedione and testosterone) are necessary precursors for estrogen synthesis to occur in the ovary. Androgens are also secreted by both ovaries and adrenals. They circulate in a concentration similar to estradiol during the preovulatory peak, and in a higher concentration during the rest of the menstrual cycle.

After menopause the secretion of progesterone and estrogens falls dramatically, but androgens continue being secreted in an even higher proportion than during the fertile period of life.

Since androgens are secreted by both ovaries and adrenal glands, they constitute the dominant sex steroid hormones throughout a woman’s entire life. The main androgen secreted is dehidropeandrosterone, both sulphated and non-sulphated (DHEA-S or DHEA, respectively), but androstenedione is also important and is a direct precursor of testosterone involved in the conversion of low-potency androgens secreted by both adrenals and ovaries into potent androgens and estradiol are expressed in many cell types, including the epithelial and stromal breast cancer cells.

Adaptation in order to survive in a low estrogenic milieu after menopause appears to be a crucial step in breast and endometrial epithelial cell biology. Such adaptation might involve both increasing the capability of local estrogen synthesis and increasing the cell responsiveness to estrogen. This change could be brought about in epithelial cells by increasing the levels of aromatase, estrogen receptors and coactivators. These adaptations would give the cells a higher capability of surviving when levels of estrogen are low, and could be at the basis of estrogen driven carcinogenesis.

Breast cancer occurs at a high frequency in women and, given this fact, a primary focus of breast cancer research has been the study of estrogen receptor signaling. However, androgens are known to play a role in some normal
breast physiology and therefore androgen receptor signaling also may be important in breast carcinogenesis. Moreover, the presence of androgen receptor in breast cancer makes it an attractive therapeutic target but the ability to exploit androgen receptor for therapy has been difficult.

This is in part because androgens can either inhibit or stimulate cell proliferation in preclinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors such as estrogen receptor and progesterone receptor which can affect androgen receptor signaling and obfuscate the effects of androgens. To elucidate the role of androgens, the work presented here reports the generation of both malignant and benign estrogen and progesterone receptor negative human breast epithelial cell lines engineered to express androgen receptor.

Experiments using these models show that concurrent hyperactivation of the mitogen activated protein (MAP) kinase pathway from androgen receptor and extracellular growth factor signaling results in an anti-proliferative response whereas MAP kinase signaling from either androgen receptor or extracellular growth factor signaling alone results in cellular proliferation. Additionally, in the benign cell line, gene knockdown and gene knockout studies demonstrate that activation of the MAP kinase pathway via androgen receptor signaling is dependent on p21. These findings provide a mechanistic explanation for previous observations ascribing a dual role for androgen receptor in breast cancer cells, and provide new insights for exploiting androgen receptor as a target for breast cancer therapy.

Although the androgen receptor (AR)3 is often co-expressed with the estrogen receptor (ER) and progesterone receptor (PR) in human breast tumors, its role in breast cancer is poorly understood. Specific growth stimulatory and inhibitory actions of androgens have been described in human breast cancer cell lines. The mechanisms by which androgens exert these contrasting growth effects are unknown. A commonly utilized second line therapy for the treatment of advanced breast cancer is high dose medroxyprogesterone acetate (MPA). Although MPA, a synthetic progestin, was thought to act exclusively through the PR, the androgenic side-effects observed in women taking MPA suggest that its action may also be mediated in part by the AR. In support of this hypothesis, the level of AR measured by radioligand binding in primary breast tumors was correlated with the duration of response to MPA treatment following failure of tamoxifen therapy. Recent data suggest that the presence of structurally altered AR in breast cancers may account for unresponsiveness to MPA in some of these cases. Further studies are warranted to determine the role of AR mediated pathways in regulating breast tumor growth. In particular, identification of androgen-regulated genes may lead to new possibilities for the hormonal treatment of breast cancer.

by Garay, Joseph P., Ph.D., THE JOHNS HOPKINS UNIVERSITY, 2010, 89 pages; 3463588
Birrell SN, Hall RE, Tilley WD. - Flinders Cancer Centre, School of Medicine, Flinders University of South Australia, Bedford Park, Australia.

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B. Nicol´as D´ıaz-Chico, F. Germ´an Rodr´ıguez, Ana Gonz´alez, Raquel Ram´ırez, Cristina Bilbao, A. Cabrera de Le´on, A. Aguirre Jaime, Ricardo Chirino, Domingo Navarro, Juan C. D´ıaz-Chico