Abstract 4962: TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells

Abstract

Abstract TLE1 is a Groucho related transcriptional repressor protein that exerts survival and anti-apoptotic function in several cellular systems and has been implicated in the pathogenesis of cancer. In the present study, we found that TLE1 is a critical regulator of anoikis in normal mammary epithelial and breast carcinoma cells. The induction of apoptosis following loss of cell attachment to the extracellular matrix (ECM) (anoikis) in untransformed mammary epithelial MCF10A cells was associated significant downregulation of TLE1 expression while forced expression of exogenous TLE1 in these cells promoted resistance to anoikis. In stark contrast, TLE1 expression was significantly upregulated following detachment from the ECM in malignant and anoikis resistant breast cancer cell lines, MDA-MB-231 and MCF7. Importantly, enforced suppression of TLE1 in these cells resulted in attenuation of anoikis resistance and decreased anchorage-independent growth with no impact on cell viability in adherent conditions. Consistently, enforced ectopic TLE1 expression further enhanced the anoikis resistance and anchorage-independent growth of MDA-MB-231 cells. The pro-survival and anti-apoptotic role of TLE1 during loss of cell attachment is in part attributed to its ability to inhibit the caspase-independent anoikis function of Bit1. Interestingly, the TLE1 protein is channelled to proteosomal degradation by Bit1 during anoikis. Taken together, these findings indicate a novel role for TLE1 in the maintenance of anoikis resistance in breast cancer cells. This conclusion is supported by an immunohistochemical analysis of a breast cancer tissue array illustrating that TLE1 is selectively upregulated in invasive breast tumors relative to noninvasive ductal carcinoma in situ (DCIS) and normal mammary epithelial tissues. 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 4962. doi:1538-7445.AM2012-4962