title: Expression of a phosphorylated p130(Cas) substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: Shefali
authors.initials: S
authors.lastname: Soni
authors.forename: Bor-Tyh
authors.initials: BT
authors.lastname: Lin
authors.forename: Avery
authors.initials: A
authors.lastname: August
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Kathrin H
authors.initials: KH
authors.lastname: Kirsch