Estrogen receptor alpha 46 is reduced in tamoxifen resistant breast cancer cells and re-expression inhibits cell proliferation and estrogen receptor alpha 66-regulated target gene transcription

Resistance to endocrine therapy is a major clinical problem in breast cancer. The role of ERα splice variants in endocrine resistance is largely unknown. We observed reduced protein expression of an N-terminally truncated ERα46 in endocrine-resistant LCC2, LCC9, and LY2 compared to MCF-7 breast cancer cells. Transfection of LCC9 and LY2 cells with hERα46 partially restored growth inhibition by TAM. Overexpression of hERα46 in MCF-7 cells reduced estradiol (E2)-stimulated endogenous pS2, cyclin D1, nuclear respiratory factor-1 (NRF-1), and progesterone receptor transcription. Expression of oncomiR miR-21 was lower in TAM-resistant LCC9 and LY2 cells compared to MCF-7 cells. Transfection with ERα46 altered the pharmacology of E2 regulation of miR-21 expression from inhibition to stimulation, consistent with the hypothesis that hERα46 inhibits ERα activity. Established miR-21 targets PTEN and PDCD4 were reduced in ERα46-transfected, E2-treated MCF-7 cells. In conclusion, ERα46 appears to enhance endocrine responses by inhibiting selected ERα66 responses.