Chunyan Hu, Manli Wang, Miao Hu, Shanshan Ma, Bingmo Yang, Wei Xiao, Qian Zhou, Ming Zhou, Zhong Li
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引用次数: 0
Abstract
Genistein (GE), the most important phytoestrogen in diet, is known to behave as a partial agonist of estrogen receptor α and shows a proliferative effect on the growth of breast cancer cell lines. Recent research has reported that long-term consumption of low doses of GE results in hormone-independent growth phenotypes of MCF-7 tumors, with increased HER2. Overexpression of HER2 has been associated with endocrine resistance in human breast cancer, but whether long-term low-level GE-induced HER2 expression is the cause of endocrine resistance remains to be determined. Short-term and long-term treatments with GE may have different effects on HER2 expression. We found that low doses of GE had estrogen-like effects and inhibited HER2 expression after short-term exposure in estrogen receptor-positive breast cancers cells. However, in contrast to short-term exposure, long-term exposure induced an increase in HER2 expression, which led to endocrine resistance. During long-term low-level exposure, the continuous activation of ERK1/2-phosphorylated EZH2 at Ser21 resulted in a decrease of lysine 27 trimethylation. As H3K27me3 levels decreased, the expression of interleukin-6 (IL-6) and IL-8 increased, and HER2 levels gradually increased, forming a feedback loop of ERK1/2/EZH2/IL-6 and IL-8/HER2. We identified a novel pathway by which EZH2 phosphorylation contributed to long-term low-level GE-induced HER2 overexpression and provided new insight for long-term low-level GE-induced acquired endocrine resistance. For breast cancer patients, long-term low-level use of soy supplements has potential health risks, and monitoring dietary exposure to GE is advisable when patients are treated with tamoxifen.
期刊介绍:
Endocrine-Related Cancer is an official flagship journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology, the United Kingdom and Ireland Neuroendocrine Society, and the Japanese Hormones and Cancer Society.
Endocrine-Related Cancer provides a unique international forum for the publication of high quality original articles describing novel, cutting edge basic laboratory, translational and clinical investigations of human health and disease focusing on endocrine neoplasias and hormone-dependent cancers; and for the publication of authoritative review articles in these topics.
Endocrine neoplasias include adrenal cortex, breast, multiple endocrine neoplasia, neuroendocrine tumours, ovary, prostate, paraganglioma, parathyroid, pheochromocytoma pituitary, testes, thyroid and hormone-dependent cancers. Neoplasias affecting metabolism and energy production such as bladder, bone, kidney, lung, and head and neck, are also considered.