Abstract 1096: Loss of miR-200 family of microRNAs confers resistance to tamoxifen in human breast cancer cells

Abstract

Abstract MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level. MiR-200 family includes two clusters i.e. miR-200 a/200b/ 429 and miR-200c/141 encoded on chromosome 1 and chromosome 12, respectively. Previous studies have demonstrated that miR-200 family targets ZEB1, a transcription factor that promotes epithelial-to-mesenchymal transition (EMT). Previous reports demonstrated a loss of miR-200a, b and c in MDA-MB-231 breast cancer cells resulted in EMT. These studies also showed a concomitant increase in ZEB1 protein. We observed lower miR-200a, b and c expression in estrogen-independent LCC1 and endocrine-resistant LCC2, LCC9, and LY2 compared to the parental, endocrine-sensitive MCF-7 human breast cancer cell line. We found that ZEB1 protein is expressed in tamoxifen-resistant LY2 cells but not in tamoxifen-sensitive MCF-7 cells. LY2 cells did not express E-cadherin, a ZEB1 target which is also a marker for epithelial phenotype. This is the first demonstration that LY2 cells have undergone EMT as part of their endocrine-resistant phenotype. These studies indicate that loss of miR-200 and a corresponding increase in ZEB1 protein is an indicator of tamoxifen-resistance in breast cancer cells. Further, in concordance with higher miR-221/222, there was decreased expression of estrogen receptor alpha (ERα) mRNA and protein in LY2 cells when compared to MCF-7 cells. We hypothesize that ERα expression is decreased in cells that have undergone EMT and this subsequently leads to endocrine-resistance and an invasive phenotype. Future studies will determine whether re-expression of ERα or knockdown of ZEB1 restores TAM-sensitivity in LY2 cells. By evaluating the expression of E-cadherin, it will be possible to determine whether restoration of ERα or knockdown of ZEB1 can revert cells from a mesenchymal to an epithelial phenotype. If validated, loss of miR-200 could be used as a marker of poor prognosis in TAM-resistant breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1096. doi:1538-7445.AM2012-1096