Browsing by Subject "Estrogen receptor alpha"

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Alcohol promotes mammary tumor development through regulation of estrogen signaling
(2012-05) Wong, Amy W.; Nuñez, Nomelí P.
Breast cancer is the most common malignancy affecting women and the second leading cause of death among women in the United States. Alcohol consumption is one of the few modifiable risk factors for breast cancer development but the mechanism by which it contributes to mammary cancer development and progression remains unclear, although it has been suggested that estrogen is critical for this process. To determine if alcohol promotes mammary tumor development via the estrogen pathway, estrogen receptor alpha-negative (ER[alpha]-negative) MMTV-neu mice were treated with various doses of ethanol and activation of estrogen signaling was measured. Our results showed that alcohol consumption increased estrogen signaling activation, serum estrogen levels and, most interestingly, expression of ER[alpha] in tumor tissue in the ER[alpha]-negative mice. Several lines of evidence in literature suggest that ER[alpha] expression in ER[alpha]-negative cancer cells is inhibited through epigenetic regulation. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than DNA sequence changes. Thus, to determine whether alcohol may regulate ER[alpha] re-expression in ER[alpha]-negative breast cancer cells through epigenetic mechanisms, we examined the effects of ethanol on CpG methylation and histone modifications (acetylation and methylation) of two ER[alpha]-negative breast cancer cell lines, MDA-MB-231 (human) and MMTV-neu (mouse). We also examined whether the epigenetic modifications subsequently affect the recruitment of transcriptional regulation complexes to the ER[alpha] promoter to regulate ER[alpha] transcription. Results showed that alcohol promotes ER[alpha] re-expression in these ER[alpha]-negative cell lines and that this effect was associated with decreased CpG methylation, an overall increase of histone acetylation and decrease of histone methylation, and an alteration in the enrichment of the ER[alpha] transcriptional regulation complexes (pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1) at the ER[alpha] promoter, which may contribute to cancer cell progression. In addition, we found that the inhibition of ER[alpha] by tamoxifen specifically blocks the effects of alcohol on ER[alpha] reactivation. To determine how alcohol promotes cell invasive ability, a critical process for cancer progression, we examined the role of two genes, metastasis suppressor Nm23 and integrin alpha-5 ITGA5, which we identified to be important for alcohol-induced breast cancer cell invasion. It has previously been shown that estrogen may regulate Nm23 expression and that estrogen regulation may be important for ITGA5-mediated cancer progression. Our results showed that alcohol promotes cancer cell invasion through the down-regulation of Nm23, which led to the subsequent increase of ITGA5 and increase of cell invasion. Collectively, data from my research strongly supports and provides evidence that alcohol promotes breast cancer development and progression through the regulation of estrogen signaling.
Estrogen and the aging brain of male rats
(2016-12) Nutsch, Victoria Lynn; Dominguez, Juan M.; Gore, Andrea C., 1964-; Hofmann, Hans; Cummings, Molly; Gonzales, Rueben
Gonadal steroid hormones exert an influence on many aspects of neurobiology in men, including memory, learning and sexual dysfunction. Though testosterone is the main circulating gonadal steroid hormone in males, estradiol is also important, and together these hormones play complementary roles. While the specific roles of estrogen have been studied to some extent in young adults, little is known during aging, when sexual behavior can become impaired. I used a rodent model to examine estradiol’s role in sexual behavior and gene expression in 3 regions, selected for their importance in behavioral neuroendocrine functions and high concentrations of estrogen receptors: the medial preoptic area (mPOA), medial amygdala (MeA), and bed nucleus of the stria terminalis (BnST). My studies focused first on how age and sexual experience affects expression and activation of estrogen receptor α (ERα) and androgen receptor (AR) after sexual behavior in aging intact males. Quantification of neurons expressing hormone receptors in the mPOA revealed that neither ERα nor androgen receptor (AR) showed an age-related change in expression in the mPOA. While both ERα and AR were activated after copulation, the age-related changes were specific to ERα in the central mPOA. There were only mild deficits in sexual behavior. Serum estradiol was also elevated in both aged and copulating animals, but estradiol concentrations only correlated with sexual behavior in aged animals. In a second study, I determined how hormone deprivation (castration) and replacement with estradiol caused changes to gene expression in the mPOA, BnST and MeA. Each region had unique patterns of gene expression in response to aging and estradiol treatment. The mPOA only had changes in expression as a result of hormone administration, while the BnST had primarily age-related changes. The MeA had the greatest number of affected genes, mainly interactions between estradiol treatment and aging. These studies emphasize the importance of estradiol in aging males, and the need for continued study on its role in neuroendocrine and sexual function.