title: 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 antiapoptotic 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 extracellular matrix. 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 proapoptotic 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 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 and normal mammary epithelial tissues.
authors.affiliation: Center for Nanomedicine, Sanford-Burnham Medical Research Institute, Santa Barbara, California, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Brunquell
authors.forename: Hector
authors.initials: H
authors.lastname: Biliran
authors.forename: Scott
authors.initials: S
authors.lastname: Jennings
authors.forename: Shubha Kale
authors.initials: SK
authors.lastname: Ireland
authors.forename: Renwei
authors.initials: R
authors.lastname: Chen
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D023102:Anoikis / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D056970:Co-Repressor Proteins; D024101:Mitochondrial Proteins; D012097:Repressor Proteins; C499043:TLE1 protein, human; C498445:TLE5 protein, human; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human