27-hydroxycholesterol induces multidrug resistance in estrogen receptor- positive breast cancer cells via elevation of HER2

Background Estrogen receptor-positive breast cancer is prone to drug resistance during endocrine therapy and chemotherapy, a complex phenomenon known as multidrug resistance (MDR). 27-Hydroxycholesterol (27HC), a main metabolite of cholesterol in the body, is conformed to be is an independent risk factor for estrogen receptor-positive breast cancer. However, the potential association of 27HC accumulation in vivo with endocrine therapy or chemotherapy resistance remains to be determined. We recently demonstrated that human epidermal growth factor receptor 2 (HER2) upregulation represents a novel mechanism underlying endocrine resistance in breast cancer. The potential role of 27HC in HER2 expression and MDR of breast cancer is currently unknown. Methods In this study, human ER-positive breast cancer cell lines with low HER2 expression, T47D and MCF-7, were used to study the effects of exposure to 27HC on MDR in breast cancer in vitro . Results Long-term exposure to 27HC clearly induced MDR in ERα-positive breast cancer cells. In terms of the underlying mechanism, 27HC-induced reactive oxygen species (ROS) promoted HER2 expression, which is an important causative factor of MDR. Based on the data, we infer that ROS activate the IL-6/STAT3 pathway through phosphorylation of ERK1/2, enhancing HER2 expression and further promoting a HER2-ERK1/2-STAT3 positive feedback loop, which ultimately leads to the development of MDR. Conclusion Our collective data indicate that 27HC interferes with endocrine therapy and chemotherapy in breast cancer, representing a novel mechanism of MDR. Accordingly, we propose that hypercholesterolemia or accumulation of 27HC in the body is a potential health risk for breast cancer patients. Moreover, HER2 may have clinical utility as an intervention target to reduce the occurrence of MDR in patients and ultimately improve the efficacy of endocrine therapy and/or chemotherapy.