Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit?

Abstract

The link between estrogen and the development and proliferation of breast cancer is well documented. Estrogen stimulates growth and inhibits apoptosis through estrogen receptor-mediated mechanisms in many cell types. Interestingly, there is strong evidence that estrogen induces apoptosis in breast cancer and other cell types. Forty years ago, before the development of tamoxifen, high-dose estrogen was used to induce tumor regression of hormone-dependent breast cancer in post-menopausal women. While the mechanisms by which estrogen induces apoptosis were not completely known, recent evidence from our laboratory and others demonstrates the involvement of the extrinsic (Fas/FasL) and the intrinsic (mitochondria) pathways in this process. We discuss the different apoptotic signaling pathways involved in E2 (17β-estradiol)-induced apoptosis, including the intrinsic and extrinsic apoptosis pathways, the NF-κB (nuclear factor-kappa-B)-mediated survival pathway as well as the PI3K (phosphoinositide 3-kinase)/Akt signaling pathway. Breast cancer cells can also be sensitized to estrogen-induced apoptosis through suppression of glutathione by BSO (L-buthionine sulfoximine). This finding has implications for the control of breast cancer with lowdose estrogen and other targeted therapeutic drugs. IntroductionBreast cancer is one of the most frequently diagnosed cancers among women, with an estimated 184,450 new cases of invasive disease and 40,930 deaths in 2008. There is strong evidence that estrogen plays a role in its development and progression [1]. Breast cancer was first recognized to be estrogen-dependent when the British surgeon George Beatson [2] published his findings of the beneficial effects of oophorectomy in a pre-menopausal patient with advanced breast cancer. Beatson had based his approach on the role of the ovaries in mammalian lactation and presumed that there would be a similar mechanism for breast cancer growth. Since that time, there has been an expanding clinical database that implicates estrogen in the development and progression of breast cancer. Evidence to support this conclusion comes from clinical studies of hormone replacement therapy, which were initially designed to determine the benefits of replacement approaches on post-menopausal women's health [3,4], and the successful clinical strategy of treating breast cancer by blocking estrogen action using the anti-estrogen tamoxifen [5] or preventing estrogen synthesis using aromatase inhibitors (AIs) [6].Estrogens are a class of sex steroid hormones that are synthesized from cholesterol and are secreted primarily by the ovaries, with secondary contributions from placenta, adipose tissue, testes, and adrenal glands. After menopause, ovarian estrogen biosynthesis is minimal, with circulating estrogens being derived principally from peripheral aromatization of adrenal androgens. Estrogens are essential to the function of the female reproductive system and are required for the proliferation and differentiation of healthy breast epithelium. Estro...

IQGAP1 modulates the proliferation and migration of vascular smooth muscle cells in response to estrogen

“…However, augmented estrogen levels have also been reported to reduce SMC migration and proliferation (17,32,33). These dual or opposite effects of estrogen have also been demonstrated in other cell types (34); however, the mechanisms invovled…”

Effects of estrogen on the proportion of stem cells in the breast

“…These results might seem paradoxical given that exposure to estrogen is considered to increase the risk of breast cancer (reviewed in [47]). Although the complexity of estrogen signaling has already been highlighted [48].…”

“…Thus, given that estrogen is required for mammary gland differentiation during puberty [51], it is possible that estrogen can have the beneficial effect of reducing the size of the mammary stem cell pool. Furthermore, clinical benefit has been observed using estrogen to treat women with metastatic breast cancer resistant to classical hormone therapy [52] and also in high doses to treat hormonally sensitive tumors [48], and higher circulating estrogen levels in postmenopausal breast cancer patients are associated with a less aggressive tumor phenotype [53].…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…ERα has strong mitogenic activity in breast cancer cells and its signaling enhances the transcriptional activation of cyclin D1 and c-Myc [227]. ERα prevents apoptosis by controlling both the extrinsic and intrinsic apoptotic pathways and by promoting cell survival [228], whereas TGF-β causes cell cycle arrest by inhibiting cyclin-dependent kinase activities and by reducing the expression levels of c-Myc in epithelial cells [228]. TGF-β can also promote apoptosis or cell survival in a cell-type and context-dependent manner [229].…”