Alcohol promotes mammary tumor development via the estrogen pathway in estrogen receptor alpha-negative HER2/neu mice

Background: Alcohol consumption is an established risk factor for breast cancer. Yet, the mechanism by which alcohol affects breast cancer development remains unresolved. The transition from the premenopausal to the postmenopausal phase is associated with a drastic reduction in systemic estrogen levels. It is not clear whether the risk of breast cancer attributable to alcohol consumption is modified by the different levels of estrogen found in pre‐ and postmenopausal women. The objective of this study is to determine whether the effects of alcohol on mammary tumor development are dependent on the presence of ovarian estrogen. Methods: As a model of breast cancer, we used mouse mammary tumor virus (MMTV)‐neu transgenic mice that overexpress the human epidermal growth factor receptor 2 (HER2/neu) in the mammary epithelium, resulting in the development of estrogen receptor alpha (ERα)‐negative mammary tumors. The mammary tumorigenesis process in these mice is similar to that of patients with HER2 breast cancer. Nonovariectomized (NOVX) and ovariectomized (OVX) MMTV‐neu mice were exposed to 0, 5, and 20% ethanol in the drinking water. Breast cancer development and progression were determined alongside the effects of alcohol on estrogen availability and signaling. Results: Our data show that 20% alcohol consumption promoted tumor development in MMTV‐neu mice only in the presence of ovarian hormones. Tumor promotion was associated with increased systemic estrogen levels, increased expression of aromatase (the rate‐limiting enzyme in estrogen synthesis), and increased expression of ERα in the tumors of 20% alcohol‐consuming MMTV‐neu mice. Additionally, we show that ovariectomy (removal of the ovaries and ovarian hormone production) blocked the effects of 20% alcohol on tumor development. Conclusions: Our results support the notion that alcohol consumption promotes HER2 breast cancer development via the estrogen signaling pathway. Additionally, they suggest that the effects of alcohol on breast cancer may be prevented by blocking estrogen signaling.