Harmful effect of ERβ on BCRP-mediated drug resistance and cell proliferation in ERα/PR-negative breast cancer.

The role of estrogen receptor (ER) in breast cancer is still under investigation. Various studies have provided evidence that ER behaves as a tumor suppressor in breast cancer, whereas some studies of estrogen receptor (ER) negative breast cancer reported a positive correlation between high ER expression and poor prognostic phenotypes, such as induced proliferation, invasion and metastasis. In the present immunohistochemistry study of 99 ER/progesterone receptor (PR)-negative breast cancer samples, nuclear expression of ER was positively associated with membranous expression of breast cancer resistance protein (BCRP), Ki67 (proliferation marker) and tumor size. Moreover, both endogenous and exogenous ER upregulated BCRP expression which induced BCRP-mediated drug resistance and enhanced proliferation of ER-/PR- breast cancer cells in the presence of 17-estradiol, whereas these effects were reversed by additional use of tamoxifen (TAM). In addition, the regulation of BCRP via specific binding between ER and estrogen response element (ERE) was demonstrated in an electrophoretic mobility shift assay. Overall, our findings manifest that ER might act as a tumor promoter of cell proliferation and BCRP-mediated drug resistance in ER-/PR- breast cancer. TAM routinely used for patients with ER+/PR+, ER+/PR- and ER-/PR+ breast cancer might also be effective in ER-/PR- but ER+ breast cancer. Therefore, the detection of ER in clinic is valuable and should not be neglected in breast cancer, especially for the ER-/PR- phenotype.