ERK-Mediated Phosphorylation of EZH2 Regulates HER2 Expression on Long-term Genistein-induced Acquired Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer Cells

Abstract

BackgroundGenistein, a soy isoflavones, is the most important phytoestrogens in typical oriental diet. Many studies have shown that genistein at lower concentrations promotes breast cancer cells growth through the estrogen receptor pathway. However, recent research has found that long-term consumption of low doses of genistein results in hormone-independent growth phenotypes of MCF-7 tumors, with increased expression of HER2. Overexpression of HER2 has been causally associated with endocrine therapy resistance in human breast cancer. The mechanism by which prolonged exposure to genistein leads to increased HER2 expression is unclear. Whether genistein-induced HER2 expression is the cause of endocrine resistance remains to be determined. MethodsWe selected the MCF-7 and T47D breast cancer cells model with higher ERα and lower HER2. It was investigated whether prolonged exposure to genistein induced TAM-sensitive breast cancer cells to TAM-refractory cells by increasing HER2 expression. Furthermore, it was explored whether HER2 expression and endocrine resistance were associated with EZH2. ResultsWe found that genistein had estrogen-like effect and inhibited HER2 expression during short-term exposure. However, long-term exposure to genistein induced acquire endocrine resistance, because of increased expression of HER2. During long-term exposure to genistein, the continuous activation of ERK1/2 phosphorylated EZH2 at Ser21, resulting in a decrease of lysine 27 trimethylation. As H3K27me3 level decreased, the expression of IL-6 and IL-8 increased, and HER2 level gradually increased, forming a feedback loop of ERK1/2 / EZH2/ IL-6 and IL-8 / HER2. ConclusionsThese findings indicated that high HER2 expression caused by EZH2 phosphorylation was an important mechanism of endocrine resistance. The study also provided a new insight for genistein-induced acquired endocrine resistance. For breast cancer patients, long-term use of soy supplements has potential health risk. Especially, monitoring dietary exposure to genistein is advisable when treated with tamoxifen.