Estrogen Action In Breast Cancer Research Articles

Coxsackie and adenovirus receptor is a target and a mediator of estrogen action in breast cancer

The involvement of the coxsackie and adenovirus receptor (CAR), an adhesion molecule known to be the main determinant of adenovirus transduction of the cells, in cancer is currently under investigation. Recent reports suggest that CAR levels are elevated in breast cancer, and this may have an impact on its use as means of delivery for gene therapy. In this study, we show that estradiol (E(2)) treatment of the estrogen receptor (ER)-positive breast cancer cell MCF-7 increases CAR levels and, in turn, enhances adenoviral transduction. Employing the transfection of CAR promoters in breast cancer cells, we show that this regulation of CAR expression occurs at the transcriptional level. In addition, and by chromatin immunoprecipitation, we have identified a crucial region of CAR promoter that controls E(2) responsiveness of CAR gene through the recruitment of ER. Moreover, utilizing CAR antibodies or CAR silencing by RNA interference repressed the estrogen-dependent growth of breast cancer cells, whereas the stable expression of CAR in MCF-7 or MDA-MB-231 cells led to an increased proliferation. Altogether, our data suggest that CAR is a novel estrogen-responsive gene, which is involved in the E(2)-dependent proliferation of breast cancer cells.

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

Because activated estrogen (ER) and androgen (AR) receptors stimulate cell proliferation in breast and prostate cancer, inhibiting their actions represents a major therapeutic goal. Most efforts to modulate ER and AR activity have focused on inhibiting the synthesis of estrogens or androgens or on the identification of small molecules that act by competing with agonist hormones for binding in the ligand-binding pocket of the receptor. An alternative approach is to implement screens for small molecule inhibitors that target other sites in the pathway of steroid receptor action. Many of these second-site inhibitors directly target ER or AR; others have still unknown sites of action. Small molecule inhibitors that target second sites represent new leads with clinical potential; they serve as novel modulators of receptor action; and they can reveal new and as yet unidentified interactions and pathways that modulate ER and AR action.

Abstract 4591: Estrogen receptor beta controls a wide variety of functions in breast cancer cells

Abstract The role of ER alpha as the mediator of estrogen action in breast cancer (BC) cells is well known, however, the role of ER beta is controversial. The majority of BC expressing ER alpha also express ER beta. Some clinical studies suggest that ER beta expression is a good prognosticator; however, in others, especially where expression levels of ER beta > ER alpha, ER beta may be associated with more advanced BC. Previously, we showed that ER beta may regulate a number of signaling pathways (AACR, 2008). Our recent work demonstrates that ER beta has even wider actions in MCF7 and T47D cells stably overexpressing ER beta. Thus, ER beta decreased phospho (p)/ total Stat1, p Stat3, p Stat5/total Stat5. Expression of the oncogenic miR cluster 17-92 was highly reduced (p<0.01) when ER beta overexpressing vs. control cells were compared. ER beta also decreased PPAR gamma, superoxide dismutase, as well as the concentration of the mRNA processing factor, RBM5, and the activated form of AMPK. All these changes were significant (p<0.05) in triplicate measurements. While ER beta overexpression increased migration through Matrigel, it significantly decreased CXCR4 expression (p<0.05, n=4). All of these effects of ER beta were estrogen-independent. On the other hand, estrogen increased CXCR4 expression in MCF7 cells significantly. In our study, we analyzed the expression of ER beta and BAD using tissue microarrays with normal and neoplastic breast tissue. Our immunohistochemical (IHC) data revealed a significant increase of ER beta cytoplasmic staining in neoplastic cells compared to normal cells (p<0.001). In addition, the nuclear expression of ER beta was significantly decreased in neoplastic cells compared to normal cells (p<0.01). From our correlation analysis of IHC data obtained from tissue microarray, we identified that cytoplasmic expression of BAD was negatively correlated with cytoplasmic expression of ER beta. In addition, the nuclear expression of BAD was significantly positively correlated with nuclear ER beta. These results suggest that ER beta has a wide variety of actions in BC cells, as predicted by the regulation of 62 miRs (p<0.01) as determined by Exiqon Inc. Taken together our results suggest that ER beta may have a multitude of actions in breast cancer and that the ratio of ER alpha/beta may determine the prognostic outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4591.

Mixed Tocopherols Prevent Mammary Tumorigenesis by Inhibiting Estrogen Action and Activating PPAR-γ

Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis. Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Estrogen receptors and their downstream targets in cancer

Estrogen has crucial roles in the proliferation of cancer cells in reproductive organs such as the breast and uterus. Estrogen-stimulated growth requires two estrogen receptors (ERalpha and ERbeta) which are ligand-dependent transcription factors. High expression of ERs is observed in a large population of breast tumors. In addition, the positive expression of ERs correlates with well-differentiated tumors, a favorable prognosis, and responsiveness to an endocrine therapy with anti-estrogen drugs in patients with breast cancer. Transcription activities of ERs can be regulated by interacting proteins such as coactivators and kinases as well as ligand-binding. Moreover, ER isoforms lacking an ability to transactivate are involved in breast cancer. Downstream target genes of ERs have important roles in mediating the estrogen action in breast cancer. We have isolated and characterized several novel estrogen-responsive genes to clarify the molecular mechanism of the estrogen action in target cells. Among these genes, the estrogen-responsive finger protein (Efp) was found to be highly expressed in breast cancer. Efp as a ubiquitin ligase (E3) is involved in the proteasome-dependent degradation of the 14-3-3sigma protein, one of cell cycle brakes, this degradation resulting in the promotion of breast cancer growth. A full understanding of the expression and function of ERs and their target genes could shed light on how estrogen stimulates the initiation and promotion of cancer, providing a new approach to diagnose and treat cancer.

Studies on mechanisms of estrogen and antiestrogen action in human breast cancer.

Studies have shown that patients whose tumors are ER (estrogen receptor) positive have at least tenfold chance of responding successfully to endocrine therapy. However, not all ER-containing tumors necessarily respond, and ERs are thus considered necessary but not sufficient markers of hormone dependence. It has been proposed that progesterone receptors (PgR) found in human breast tumors may serve as a marker of estrogen action in breast cancer, since PgR synthesis is known to be controlled by estrogens in the uterus. The authors have recently worked on a modal system which shows that PgR are under estrogen control and that PgR synthesis involves the ER. Their study concerning the effects of antiestrogens show that tamoxifen (TAM) is a potent inducer of PgR on the cells and that TAM's estrogenic property is masked at very high doses (1 mcg/M) which also inhibit cell growth. Nafoxidine (NAF), another antiestrogen, had little effect on PgR when tested over a wide dose range. It has been reported that growth-inhibitory effects of both antiestrogens can be reversed by estradiol; this indicates that the effects of these compounds are mediated through the ER system. A complex system in cells in which ER binding and translocation and turnover of nuclear receptors or their processing mediate the induction of PgR by estradiol is described.