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Expression of a phosphorylated p130 Cas substrate domain attenuates the phosphatidylinositol 3‐kinase/Akt survival pathway in tamoxifen resistant breast cancer cells
Author(s) -
Soni Shefali,
Lin BorTyh,
August Avery,
Nicholson Robert I.,
Kirsch Kathrin H.
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22136
Subject(s) - antiestrogen , protein kinase b , cancer research , signal transduction , tamoxifen , kinase , biology , pi3k/akt/mtor pathway , microbiology and biotechnology , medicine , cancer , breast cancer
Elevated expression of p130 Cas /BCAR1 (breast cancer anti estrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. Specifically, p130 Cas signaling has been associated with antiestrogen resistance, for which the mechanism is currently unknown. TAM‐R cells, which were established by long‐term exposure of estrogen (E 2 )‐dependent MCF‐7 cells to tamoxifen, displayed elevated levels of total and activated p130 Cas . Here we have investigated the effects of p130 Cas inhibition on growth factor signaling in tamoxifen resistance. To inhibit p130 Cas , a phosphorylated substrate domain of p130 Cas , that acts as a dominant‐negative (DN) p130 Cas molecule by blocking signal transduction downstream of the p130 Cas substrate domain, as well as knockdown by siRNA was employed. Interference with p130 Cas signaling/expression induced morphological changes, which were consistent with a more epithelial‐like phenotype. The phenotypic reversion was accompanied by reduced migration, attenuation of the ERK and phosphatidylinositol 3‐kinase/Akt pathways, and induction of apoptosis. Apoptosis was accompanied by downregulation of the expression of the anti‐apoptotic protein Bcl‐2. Importantly, these changes re‐sensitized TAM‐R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest that targeting the product of the BCAR1 gene by a peptide which mimics the phosphorylated substrate domain may provide a new molecular avenue for treatment of antiestrogen resistant breast cancers. J. Cell. Biochem. 107: 364–375, 2009. © 2009 Wiley‐Liss, Inc.