Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells.
Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells.
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DOI：
10.1371/journal.pone.0145061
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lin CY
中科院分区：
文献类型：
--
作者：
Candelaria NR;Weldon R;Muthusamy S;Nguyen-Vu T;Addanki S;Yoffou PH;Karaboga H;Blessing AM;Bollu LR;Miranda RC;Lin CY
遗传、激素和行为因素会导致乳腺癌的发生。饮酒是一种可改变的行为，与乳腺癌风险增加有关，并与激素依赖性乳腺癌的发生以及内分泌治疗后的疾病进展和复发有关。在这项研究中，我们通过应用分子、遗传学和基因组方法来研究酒精作用的分子机制，以表征酒精对雌激素受体 (ER) 阳性乳腺癌细胞的影响。酒精治疗促进细胞增殖，增加生长因子信号传导，并上调 ER 靶基因 GREB1 的转录，但不上调经典靶基因 TFF1/pS2。酒精治疗后的微阵列分析发现了大量酒精反应基因，包括那些在细胞凋亡和细胞增殖途径中发挥作用的基因。此外，肿瘤中反应基因组的表达谱与接受内分泌治疗的患者的临床结果密切相关。相应地，酒精治疗减弱了内分泌治疗药物他莫昔芬对 ER 阳性乳腺癌细胞的抗增殖作用。为了确定反应基因的贡献和功能，评估了结果组之间它们在肿瘤中的差异表达。原癌基因 BRAF 被确定为一种新的酒精和雌激素诱导基因，在预后不良的患者中表现出较高的表达。此外，BRAF 的敲除可以阻止乳腺癌细胞的增殖。这些发现不仅强调了酒精对乳腺癌细胞影响以及增加疾病发生和复发风险的机制基础，而且可能有助于乳腺癌研究和治疗中新的致癌途径和标记物的发现和表征。
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.