Abstract 1306: Two distinct regulatory mechanisms underlie estrogen receptor negative breast cancer susceptibility at the 2p23.2 locus

Abstract The progesterone receptor (PR) plays roles in normal mammary development and breast cancer formation, where it may exert both stimulatory and inhibitory actions. Previously, the breast cancer susceptibility gene product BRCA1 was found to interact with and inhibit the transcriptional activity of estrogen receptor-α. In this study, we found that exogenous wild-type BRCA1 inhibited the activity of the PR in transient transfection assays utilizing a mouse mammary tumor virus-Luc reporter. Wild-type BRCA1 inhibited the activity of endogenous PR in human breast cancer cells (T47D and MCF-7) and inhibited the activity of exogenous PR-A, PR-B, and [PR-A plus PR-B] isoforms. On the other hand, knockdown of endogenous BRCA1 using small interfering RNA enhanced the progesterone-stimulated activity of the PR by about 4-fold. We documented an in vivo association of the endogenous BRCA1 with PR isoforms A and B and a direct in vitro interaction between BRCA1 and PR, which was partially mapped. Whereas down-regulation of the coactivator p300 contributes to the BRCA1-mediated repression of estrogen receptor-α, this mechanism does not contribute to inhibition of PR activity, because exogenous p300 did not rescue the BRCA1 repression of PR activity. The BRCA1-PR interaction has functional consequences. Thus, we showed that BRCA1 inhibits the expression of various endogenous progesterone-responsive genes and inhibits progesterone-stimulated proliferation of T47D cells. Finally, exogenous progesterone caused an exaggerated proliferative response in the mammary glands of mice harboring a mammary-targeted conditional deletion of the full-length isoform of Brca1. These findings suggest that BRCA1 regulates the activity of progesterone, a major hormone of pregnancy that may also participate in mammary carcinogenesis.

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Impact of ESR1 Polymorphisms on Risk of Breast Cancer in the Chinese Han Population

10.21203/rs.2.16623/v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ying Wei ◽

Xiaolin Wang ◽

Zhe Zhang ◽

Changtao Zhao ◽

Yuwei Chang ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Genetic Models ◽

Chinese Han ◽

Han Population ◽

Esr1 Gene

Abstract Background The Estrogen receptor-1 (ESR1) gene encodes estrogen receptor-α which is a major biomarker in the development of breast cancer. This research aimed to investigate the effect of ESR1 polymorphisms on breast cancer in Chinese Han women.Methods Four candidate single nucleotide polymorphisms (SNPs) in ESR1 gene among 503 breast cancer patients and 503 healthy people were genotyped using Agena MassARRAY platform. The association between ESR1 polymorphisms and breast cancer risk was evaluated using odds ratio (OR) and 95% confidence intervals (95% CIs) in four genetic models. The HaploReg v4.1 and GEPIA database were used for SNP functional annotation and ESR1 expression analysis respectively.Results The allele T of rs9383938 in ESR1 was significantly associated with an increased breast cancer risk (OR = 1.26, 95% CI = 1.05 – 1.50, p = 0.013). In genetic models, rs9383938 increased breast cancer risk in codominant model (OR = 1.54, 95% CI = 1.07 – 2.22, p = 0.021), dominant model (OR = 1.31, 95% CI = 1.01 – 1.68, p = 0.040), and additive model (OR = 1.24, 95% CI = 1.04 – 1.48, p = 0.017). Stratification analysis showed that rs9383938 and rs2228480 raised the breast cancer susceptibility at age < 50 years. Rs1801132 of ESR1 was also associated with the status of ER, PR, and Her-2 in allele model and genetic models significantly.Conclusion This study demonstrated that ESR1 polymorphisms might influence breast cancer susceptibility in Chinese Han population. Further mechanisms studies are needed to confirm the contribution of ESR1.

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