Abstract P6-07-31: Molecular mechanism of alcohol-associated breast cancer

Abstract

Abstract Epidemiological studies have indicated that alcohol consumption is an established risk factor for breast cancer. The association of alcohol consumption and breast cancer is more pronounced in ER+ cases than in ER- cases. However, this molecular mechanism remains to be determined. Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, increasing translational capacity to promote cell transformation and tumor formation. Our results reveal that alcohol increases Pol III gene transcription in both normal and cancer breast cell lines. The induction of Pol III genes by alcohol in ER+ breast cancer cells is significantly higher than in ER- normal breast cells and ER- breast cancer cells. E2 causes slight increase in Pol III gene transcription. The addition of ethanol to this system produces a marked increase. Alcohol increases ERa expression to enhance the cellular levels of Brf1 protein and mRNA. In addition, ethanol markedly stimulates phosphorylation of JNK1. Inhibition of JNK1 decreases ERE-Luc reporter activity and represses expression of ERa, Brf1 and Pol III genes. Reduction of ERa by its siRNA represses Brf1 and Pol III gene transcription. Ethanol with E2 produces larger and more numerous colonies. Repression of ERa or Brf1 inhibits alcohol-induced cell transformation. More interestingly, human biopsies studies show that Brf1 expression is significantly increased in nuclei of breast cancer cells, compared to tissue adjacent to the carcinoma. Together, these results support the idea that alcohol increases ERa expression through JNK1 pathway to elevate Brf1 expression and Pol III gene transcription, leading to greater phenotypic changes. ERa mediates Pol III gene transcription through Brf1, suggesting that ERa play a critical role in alcohol-induced deregulation of Pol III genes in ER+ breast cancer development. *: The project is supported by NIAAA/NIH grants: AA017288, AA021114 and AA02324 to S Zhong. Citation Format: Zhong S, Zhang Y, Lei J, Li W, Wu Z, Shi G. Molecular mechanism of alcohol-associated breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-31.