Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines.
Epidemiological studies suggest that moderate alcohol consumption increases the risk of breast cancer, and that alcohol combined with estrogen replacement therapy may synergistically enhance the risk. However, the mechanism(s) of alcohol-induced mammary cancer is unknown. In human breast cancer cell lines, we found that ethanol (EtOH) caused a dose-dependent increase of up to 10- to 15-fold in the transcriptional activity of the liganded estrogen receptor (ER-alpha), but did not activate the nonliganded receptor. Significant stimulation of ER-alpha activity was observed at EtOH concentrations comparable with or less than blood alcohol levels associated with intoxication and at doses below the threshold for in vitro cytotoxicity. These findings may be explained, in part, by an EtOH-induced down-regulation of the expression of BRCA1, a potent inhibitor of ER-alpha activity, and, in part, by a modest increase in the ER-alpha levels. Our findings suggest that inactivation of BRCA1 and increased estrogen-responsiveness might contribute to alcohol-induced breast cancer.
Fan
S
S
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA. fan@lij.edu
Meng
Q
Q
Gao
B
B
Grossman
J
J
Yadegari
M
M
Goldberg
I D
ID
Rosen
E M
EM
D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha; D000431:Ethanol / Q000009:adverse effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019398:Genes, BRCA1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D000431:Ethanol