Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells

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.

Alcohol consumption and breast tumor gene expression

“…RNA splicing or transport) has been shown to affect cell cycle and proliferation [ 29 ], although increased RNA processing also may be a consequence of proliferation. Our finding is consistent with experimental studies in which ethanol promoted proliferation in ER+ breast tumor cell lines [ 30 – 32 ]. In ER+ tumors, we also observed downregulation of lipid metabolism, including the PPAR-gamma signaling pathway.…”

Alcohol promotes migration and invasion of triple‐negative breast cancer cells through activation of p38 MAPK and JNK

“…It was previously reported that alcohol stimulates cell proliferation in ER-positive breast cancer cells [50]. The alcohol-induced phenotypic changes that we report in the TNBC cells include increased cell proliferation, migration, and invasion.…”

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

“…Alcohol and smoking have a potentiating role on E2 and oxidative stress signaling, a fact which warrants large scale studies with natural phytochemicals to assess the impact on BC incidence and associated markers of BC risk . The alcohol induced folate deficiency and consequent decline in cellular methionine synthesis could lead to reprogramming of gene expression, an area in which detailed studies are warranted to assess the impact on BC‐specific gene expression . In addition, global hypomethylation in leukocytes has been shown to be associated with increased risk for BC .…”

“…55,56 A study on alcohol in ER 1 MCF7 BC cells revealed a positive effect on proliferation and attenuated response to tamoxifen therapy which was mediated by an upregulation of BRAF, a clinical marker of poor response to endocrine therapy in BC. 57,58 Alcohol intake also raises plasma IGF-II, may enhance susceptibility to mammary carcinogenesis and increase invasiveness of BC cells. [58][59][60][61] Obesity represents a chronic proinflammatory condition.…”

“…[54][55][56] The alcohol induced folate deficiency and consequent decline in cellular methionine synthesis could lead to reprogramming of gene expression, an area in which detailed studies are warranted to assess the impact on BC-specific gene expression. 57 In addition, global hypomethylation in leukocytes has been shown to be associated with increased risk for BC. 172 Though folate can ameliorate methionine deficiency, the alcohol-induced defects in intestinal folate absorption is a limitation for oral folate supplementation.…”