Pan Shawn, Yuan Chaoshen, Tagmount Abderrahmane, Rudel Ruthann A, Ackerman Janet M, Yaswen Paul, Vulpe Chris D, Leitman Dale C
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA.
Environ Health Perspect. 2016 May;124(5):563-9. doi: 10.1289/ehp.1409200. Epub 2015 Oct 27.
Xenoestrogens are synthetic compounds that mimic endogenous estrogens by binding to and activating estrogen receptors. Exposure to estrogens and to some xenoestrogens has been associated with cell proliferation and an increased risk of breast cancer. Despite evidence of estrogenicity, parabens are among the most widely used xenoestrogens in cosmetics and personal-care products and are generally considered safe. However, previous cell-based studies with parabens do not take into account the signaling cross-talk between estrogen receptor α (ERα) and the human epidermal growth factor receptor (HER) family.
We investigated the hypothesis that the potency of parabens can be increased with HER ligands, such as heregulin (HRG).
The effects of HER ligands on paraben activation of c-Myc expression and cell proliferation were determined by real-time polymerase chain reaction, Western blots, flow cytometry, and chromatin immunoprecipitation assays in ERα- and HER2-positive human BT-474 breast cancer cells.
Butylparaben (BP) and HRG produced a synergistic increase in c-Myc mRNA and protein levels in BT-474 cells. Estrogen receptor antagonists blocked the synergistic increase in c-Myc protein levels. The combination of BP and HRG also stimulated proliferation of BT-474 cells compared with the effects of BP alone. HRG decreased the dose required for BP-mediated stimulation of c-Myc mRNA expression and cell proliferation. HRG caused the phosphorylation of serine 167 in ERα. BP and HRG produced a synergistic increase in ERα recruitment to the c-Myc gene.
Our results show that HER ligands enhanced the potency of BP to stimulate oncogene expression and breast cancer cell proliferation in vitro via ERα, suggesting that parabens might be active at exposure levels not previously considered toxicologically relevant from studies testing their effects in isolation.
Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. 2016. Parabens and human epidermal growth factor receptor ligand cross-talk in breast cancer cells. Environ Health Perspect 124:563-569; http://dx.doi.org/10.1289/ehp.1409200.
外源性雌激素是一类合成化合物，可通过与雌激素受体结合并激活该受体来模拟内源性雌激素。接触雌激素及某些外源性雌激素与细胞增殖及乳腺癌风险增加有关。尽管有证据表明对羟基苯甲酸酯具有雌激素活性，但它却是化妆品和个人护理产品中使用最为广泛的外源性雌激素之一，并且通常被认为是安全的。然而，先前基于细胞的对羟基苯甲酸酯研究并未考虑雌激素受体α（ERα）与人类表皮生长因子受体（HER）家族之间的信号转导交互作用。
我们研究了如下假设，即对羟基苯甲酸酯的效力可因HER配体（如这里生长因子，HRG）而增强。
通过实时聚合酶链反应、蛋白质免疫印迹、流式细胞术及染色质免疫沉淀试验，在ERα和HER2阳性的人BT-474乳腺癌细胞中，确定HER配体对对羟基苯甲酸酯激活c-Myc表达及细胞增殖的影响。
对羟基苯甲酸丁酯（BP）和HRG可使BT-474细胞中的c-Myc mRNA和蛋白质水平协同增加。雌激素受体拮抗剂可阻断c-Myc蛋白质水平的协同增加。与单独使用BP的效果相比，BP与HRG的组合也可刺激BT-474细胞增殖。HRG降低了BP介导的c-Myc mRNA表达及细胞增殖刺激所需的剂量。HRG导致ERα的丝氨酸167磷酸化。BP和HRG使ERα募集到c-Myc基因的过程协同增加。
我们的结果表明，HER配体可增强BP在体外通过ERα刺激癌基因表达及乳腺癌细胞增殖的效力，这表明对羟基苯甲酸酯在暴露水平下可能具有活性，而此前在单独测试其作用的研究中并未将该暴露水平视为具有毒理学相关性。
Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. 2016. Parabens and human epidermal growth factor receptor ligand cross-talk in breast cancer cells. Environ Health Perspect 124:563-569; http://dx.doi.org/10.1289/ehp.1409200.
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