Mechanisms of Increased ERalpha+ Breast Cancer Risk Due to Alcohol Consumption
Introduction. Breast cancer is the leading cause of female cancer mortality worldwide1. Overall, 1 out of every 8 women in the US will be diagnosed with breast cancer during her lifetime1. Some known risk factors linked to breast cancer include age, race, hormone usage, tobacco, fitness, and diet1. Studies show a correlation between specific amounts of daily alcohol consumption and increased risk of breast cancer2,3. For instance, breast cancer risk increases 4-15% with light consumption of alcohol (<1 drink a day) and increases 7-10% for every 10g of alcohol (about one drink) consumed per day1. Furthermore, it appears that ethanol only stimulates proliferation in ER+, and not ER– breast cancer cells.4 However, the specific mechanism in which alcohol contributes to this increased risk has not been defined and is not completely understood1,5. Methods. To investigate the mechanism by which alcohol promotes cell transformation, MCF-7 breast cancer cells were incubated with various concentrations of ethanol. Western blot analysis was performed to assess expression of JNK1, pJNK1, and Brf16. Similarly, to investigate the effects of Pol III gene transcription and deregulation, MCF-7 cells were incubated with ethanol, which more than doubled the amounts of Pol III transcripts (specifically pre-tRNA and 5S-rRNA) detecteded6. Finally, long-term ethanol exposure was assessed utilizing MCF-7 cells exposed to ethanol for 4 weeks and then transferred to a soft agar assay to measure anchorage-independent growth7. Results. Alcohol increases transcription of Brf1 in ER+ breast cancer cells by almost 200% via JNK1 activation6. Increased Brf1 expression leads to deregulation of RNA Pol III gene transcription6,8. Deregulation of RNA Pol III allows overexpression of tRNA and 5S rRNA (more than doubling the levels of each of the transcripts), which leads to increased rate and capacity of protein translation within the breast cancer cell6. Increased translation promotes cell proliferation and transformation, ultimately leading to a 5.6-fold increase in anchorage-independent growth, and tumor development7. Conclusions. The studies provided evidence supporting a specific mechanism of tumor progression in MCF-7 cells due to alcohol exposure that had not previously been hypothesized. These results indicate that the risk of developing breast cancer may be directly increased by drinking alcohol, especially consuming large daily amounts (two drinks or more per day). Increasing public and physician awareness of these findings may help at risk populations, such as women that have higher genetic susceptibility to breast cancer and women who struggle with alcoholism.
- Winters S., Martin C., Murphy D., Shokar, N.K. (2017) Breast Cancer Epidemiology, Prevention, and Screening. Prog Mol Biol Tranl Sci 151:1-23
- Huang, C., Zhang, Y., & Zhong, S. (2019). Alcohol Intake and Abnormal Expression of Brf1 in Breast Cancer. Oxidative medicine and cellular longevity, 2019.
- Moo, T. A., Sanford, R., Dang, C., & Morrow, M. (2018). Overview of breast cancer therapy. PET clinics, 13(3), 339-354.
- Jung, S., Wang, M., Anderson, K., Baglietto, L., Bergkvist, L., Bernstein, L., … & Falk, R. (2016). Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. International journal of epidemiology, 45(3), 916-928.
- Liu, Y., Nguyen, N., & Colditz, G. A. (2015). Links between alcohol consumption and breast cancer: a look at the evidence. Women’s health, 11(1), 65-77.
- Yi, Y., Huang, C., Zhang, Y., Tian, S., Lei, J., Chen, S., … & Zhong, S. (2017). Exploring a common mechanism of alcohol-induced deregulation of Brf1 and RNA Pol III genes in liver and breast cells. Gene, 626, 309-318.
- Gelfand, R., Vernet, D., Bruhn, K. W., Sarkissyan, S., Heber, D., Vadgama, J. V., & Gonzalez-Cadavid, N. F. (2017). Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features. International journal of oncology, 50(1), 49-65.
- Fang, Z., Yi, Y., Shi, G., Li, S., Chen, S., Lin, Y., … & Zhong, S. (2017). Role of Brf1 interaction with ER α, and significance of its overexpression, in human breast cancer. Molecular oncology, 11(12), 1752-1767.