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 ER alpha splice variants in endocrine resistance is largely unknown. We observed reduced protein expression of an N-terminally truncated ER alpha 46 in endocrine-resistant LCC2, LCC9, and LY2 compared to MCF-7 breast cancer cells. Transfection of LCC9 and LY2 cells with hER alpha 46 partially restored growth inhibition by TAM. Overexpression of hER alpha 46 in MCF-7 cells reduced estradiol (E(2))-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 ER alpha 46 altered the pharmacology of E(2) regulation of miR-21 expression from inhibition to stimulation, consistent with the hypothesis that hER alpha 46 inhibits ER alpha activity. Established miR-21 targets PTEN and PDCD4 were reduced in ER alpha 46-transfected, E(2)-treated MCF-7 cells. In conclusion, ER alpha 46 appears to enhance endocrine responses by inhibiting selected ER alpha 66 responses. (C) 2010 Elsevier Ireland Ltd. All rights reserved.