Tamoxifen represses alcohol-induced transcription of RNA polymerase III-dependent genes in breast cancer cells.
Alcohol consumption in women has been associated with an increased risk of breast cancer, particular in estrogen receptor positive (ER+) cases. Deregulation of RNA polymerase III-dependent (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, leading to an increase in translational capacity to promote cell transformation and tumor formation. Our recent studies demonstrated that alcohol induces Brf1 expression and Pol III gene transcription via ER. Here, we report that Tamoxifen (Tam) inhibits the induction of Brf1 and Pol III genes in ER+ breast cancer cells. Further analysis indicates that alcohol increases c-Jun expression to upregulate the transcription of Brf1 and Pol III genes, whereas Tam reduces c-Jun expression to repress the transcription of Brf1. Repression of cJun decreases cellular levels of ERα and Brf1. Alcohol-dependent increased occupancy of Brf1 in Pol III gene promoters is reduced by Tam. The repression of Brf1 and Pol III genes by Tam reduces alcohol-induced cell proliferation and colony formation. Together, these results indicate that Tam inhibits alcohol-induced Brf1 expression through c-Jun and ERα to downregulate Pol III gene transcription. Our studies uncover a new mechanism of Tam-treated ER+ breast cancer, by which Tam inhibits tumor growth through repressing Pol III gene transcription.
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.
Qian
Q
Zhong
Shantou University Medical College, Shantou, Guangdong, China.
Ganggang
G
Shi
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Qingsong
Q
Zhang
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Lei
L
Lu
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Daniel
D
Levy
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.
Shuping
S
Zhong
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000431:Ethanol / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D012320:RNA Polymerase III / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D035381:TATA-Binding Protein Associated Factors / Q000096:biosynthesis; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection
C441028:BRF1 protein, human; D011960:Receptors, Estrogen; D035381:TATA-Binding Protein Associated Factors; D013629:Tamoxifen; D000431:Ethanol; D012320:RNA Polymerase III