title: Alteration of BRCA1 expression affects alcohol-induced transcription of RNA Pol III-dependent genes.
abstract: Emerging evidence has indicated that alcohol consumption is an established risk factor for breast cancer. Deregulation of RNA polymerase III (Pol III) transcription enhances cellular Pol III gene production, leading to an increase in translational capacity to promote cell transformation and tumor formation. We have reported that alcohol intake increases Pol III gene transcription to promote cell transformation and tumor formation in vitro and in vivo. Studies revealed that tumor suppressors, pRb, p53, PTEN and Maf1 repress the transcription of Pol III genes. BRCA1 is a tumor suppressor and its mutation is tightly related to breast cancer development. However, it is not clear whether BRCA1 expression affects alcohol-induced transcription of Pol III genes. At the present studies, we report that restoring BRCA1 in HCC 1937 cells, which is a BRCA1 deficient cell line, represses Pol III gene transcription. Expressing mutant or truncated BRCA1 in these cells does not affect the ability of repression on Pol III genes. Our analysis has demonstrated that alcohol induces Pol III gene transcription. More importantly, overexpression of BRCA1 in estrogen receptor positive (ER+) breast cancer cells (MCF-7) decreases the induction of tRNA(Leu) and 5S rRNA genes by alcohol, whereas reduction of BRCA1 by its siRNA slightly increases the transcription of the class of genes. This suggests that BRCA1 is associated with alcohol-induced deregulation of Pol III genes. These studies for the first time demonstrate the role of BRCA1 in induction of Pol III genes by alcohol and uncover a novel mechanism of alcohol-associated breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
authors.affiliation: Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Shantou University Medical College, Shantou, Guangdong, China. Electronic address: szhong@usc.edu.
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhong
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D012320:RNA Polymerase III / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000431:Ethanol; D012320:RNA Polymerase III
keywords: Alcohol; BRCA1; Breast cancer; Pol III genes