Abstract
Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.
Highlights
This year, more than 230,000 women in the US will develop breast cancer, currently one of the most common causes of cancer deaths in American women (Cancer Facts and Figures, American Cancer Society, 2014)
MCF-7 breast cancer cells were primarily used in these studies because they are derived from the breast tumor subtype most commonly associated with alcohol consumption (ER+/progesterone receptor (PR)+)
These results showed that 21.7 mmol/L (0.1%) alcohol increased cell proliferation in MCF-7 cells only in the presence of estrogen (Fig 1A)
Summary
This year, more than 230,000 women in the US will develop breast cancer, currently one of the most common causes of cancer deaths in American women (Cancer Facts and Figures, American Cancer Society, 2014). Many environmental factors are known to increase breast cancer risk, including modifiable behaviors such as alcohol consumption. Epidemiological studies have strongly linked alcohol consumption to increased breast cancer risk [1,2,3,4]. These studies show that breast cancer risk is positively correlated with the amount of alcohol consumed. Alcohol consumption positively correlates with increases in breast area covered by dense parenchymal tissue and decreased β-carotene circulation, parameters which are individually known to result in increased breast cancer risk [5,6,7,8]. Given the popularity of alcohol consumption among women in the United States and a significant number of those with alcohol use disorder, alcohol consumption is a key modifiable factor in the development of breast cancer
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