Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Division of Epidemiology & Biostatistics, School of Public Health, San Diego State University, San Diego, California, USA.
Endocr Relat Cancer. 2019 Dec;26(12):843-851. doi: 10.1530/ERC-19-0357.
Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast cancer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 genes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEP-responsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2-0.5) and TMC4 (HR 0.37, 95% CI: 0.3-0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3-0.5) and NTN4 (HR 0.39, 95% CI: 0.3-0.6)) are well-known predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3-0.9 for hormonal receptor-positive and HR 3.2, 95% CI 1.7-6.2 for -negative group). In conclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer.
环境酚类和邻苯二甲酸酯是个人护理产品中的常见成分，其中一些已被牵连到乳腺癌的进展中。我们之前已经确定了在大鼠模型中对低剂量邻苯二甲酸二乙酯（DEP）和对羟基苯甲酸甲酯（MPB）暴露有反应的差异表达基因。在此，我们探讨这些基因是否与人类乳腺癌死亡率有关。我们通过 NanoString®对来自 606 名患有首次原发性乳腺癌的人群队列的肿瘤中的 MPB 和 DEP 反应基因进行了分析，其中 119 名乳腺癌特异性死亡发生在 15 年以上的随访期间。对于每个基因，使用 Cox 比例风险模型来估计风险比（HR）和 95％置信区间（CI）。结果在两个公开可用的数据集进行了验证。得到了以下结果。在所分析的 107 个 DEP 和 77 个 MPB 反应基因中，分别有 44 个和 30 个基因与乳腺癌特异性死亡率显著相关。一些顶级的 DEP 反应基因是乳腺癌死亡率的新发现，例如 ABHD14B（高表达与低表达相比，HR 0.36，95％CI：0.2-0.5）和 TMC4（HR 0.37，95％CI：0.3-0.5）；MPB 的顶级命中（SLC40A1（HR 0.37，95％CI：0.3-0.5）和 NTN4（HR 0.39，95％CI：0.3-0.6））是乳腺癌生存的已知预测因子。PLEKHA6 是另一个新的生存预测因子，对激素受体状态敏感（激素受体阳性的 HR 0.5，95％CI 0.3-0.9，激素受体阴性的 HR 3.2，95％CI 1.7-6.2）。总之，DEP 和 MPB 反应基因的肿瘤表达与乳腺癌死亡率有关，这支持接触这些化学物质可能会影响乳腺癌的进展。
