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

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