TLE1 Is an Anoikis Regulator and Is Downregulated by Bit1 in Breast Cancer Cells

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 regulator of anoikis in normal mammary epithelial and breast carcinoma cells. The induction of apoptosis following loss of cell attachment to the extracellular matrix (anoikis) in untransformed mammary epithelial MCF10A cells was associated with significant downregulation of TLE1 expression. Forced expression of exogenous TLE1 in these cells promoted resistance to anoikis. In breast cancer cells, TLE1 expression was significantly upregulated following detachment from the ECM. Genetic manipulation of TLE1 expression via overexpression and downregulation approaches indicated that TLE1 promotes the anoikis resistance and anchorage-independent growth of breast carcinoma cells. Mechanistically, we show that TLE1 inhibits the Bit1 anoikis pathway by reducing the formation of the pro-apoptotic Bit1-AES complex in part through sequestration of AES in the nucleus. The mitochondrial release of Bit1 during anoikis as well as exogenous expression of the cytoplasmic localized Bit1 or its cell death domain (CDD) induced cytoplasmic translocation and degradation of nuclear TLE1 protein. 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.

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer

“…This suggests an oncogenic effect of TLE1 in breast carcinogenesis. These findings are similar to those reported previously in gastric, breast, and lung cancer [161718]. …”

“…TLE1 overexpression has been documented in some epithelial cancers, including gastric cancer, breast cancer, lung cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma [1617181920212223]. Conflicting results have been published on the function of TLE1 in some carcinomas.…”

PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells

“…Anoikis is the process by which apoptosis occurs as a result of loss of adhesion to adjacent cells or the extracellular matrix [40, 41]. Epithelial cells are more susceptible than fibroblasts to anoikis; indeed, normal MCF-10A mammary epithelial cells undergo anoikis following loss of cell attachment, whereas MCF-7 cells show resistance [42]. Therefore, the sensitivity of cells to anoikis is inversely associated with their capacity for transformation [41].…”

Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells

“…Primary mouse tumor cells (2×10 5 cells) or MDA-MB-231 cells (1×10 6 cells) were seeded into each well that was coated by incubating with 1 ml of 6 mg/ml poly (2-hydroxyethyl methacrylate) (pHEMA), and then dried overnight in the hood, as reported early (Brunquell et al, 2012). Cells were cultured in 10% FBS DMEM medium in the presence or absence of DMSO or PLD2 inhibitor (5 μM).…”