Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

The expression of estrogen receptor-alpha (ER alpha) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ER alpha-36 has been identified as a novel variant of ER-alpha. ER alpha-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ER alpha-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ER alpha-36 by BMP2 was significant. In MDA-MB-231 cells which are ER alpha-66-negative, BMP2 was able to induce the expression of ER alpha-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ER alpha-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-beta-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ER alpha-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.