p130Cas as a New Regulator of Mammary Epithelial Cell Proliferation, Survival, and HER2-Neu Oncogene–Dependent Breast Tumorigenesis

Abstract

To investigate the mechanisms through which p130Cas adaptor protein is linked to tumorigenesis, we generated mouse mammary tumor virus (MMTV)-p130Cas mice overexpressing p130Cas in the mammary gland. MMTVp130Cas transgenic mice are characterized by extensive mammary epithelial hyperplasia during development and pregnancy and by delayed involution at the end of lactation. These phenotypes are associated with activation of Src kinase, extracellular signalregulated kinase 1/2, mitogen-activated protein kinase, and Akt pathways, leading to an increased rate of proliferation and a decreased apoptosis. A double-transgenic line derived from crossing MMTV-p130Cas with MMTV-HER2-Neu mice expressing the activated form of the HER2-Neu oncogene develops multifocal mammary tumors with a significantly shorter latency than the HER2-Neu parental strain alone. Mammary epithelial cells isolated from tumors of double-transgenic mice display increased tyrosine phosphorylation, c-Src, and Akt activation compared with cells derived from HER2-Neu tumors. In addition, p130Cas down-regulation by RNA interference increases apoptosis in HER2-Neu-expressing cells, indicating that p130Cas regulates cell survival. Consistently with the double-transgenic mice model, p130Cas is overexpressed in a significant subset of human breast cancers and high levels of p130Cas in association with HER2 expression correlate with elevated proliferation. These findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells. Its overexpression contributes to HER2-Neu-induced breast tumorigenesis, thus identifying this protein as a putative target for clinical therapy. (Cancer Res 2006; 66(9): 4672-80)

Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells

“…Focal adhesions, the sites where the actin cytoskeleton is linked to the ECM by integrin/receptor complexes, contribute to cell anchorage and to the recruitment of signalling complexes that are involved in a broad range of cellular processes, including migration, proliferation, transformation and apoptosis. Remarkably, Src family kinases have been reported to act downstream of the modifications of the integrin/ ECM complexes that contribute to neoplastic transformation (O'Neill et al 2000, McLean et al 2003, Cabodi et al 2006. Although the role of adhesion molecules is also recognized in endocrine cancer cells (Ezzat & Asa 2005), no data are currently available in PETs.…”

Integrin signalling adaptors: not only figurants in the cancer story

“…Nevertheless, investigation of its expression in biopsies of different human malignancies using immunohistochemistry is still limited to breast cancer and haematological malignancies (Table I). Recently it has been reported that in human breast cancers overexpression of both ERBB2 and p130CAS is associated with increased proliferation, metastasis formation and poor prognosis 13,14 (Table I). Consistently, double transgenic mice overexpressing both p130CAS and ERBB2 in the mammary gland show an accelerated onset of tumour formation, providing evidence that p130CAS and the ERBB2 oncogene synergise in vivo to transform the mammary epithelium 13 (Table II).…”

“…Recently it has been reported that in human breast cancers overexpression of both ERBB2 and p130CAS is associated with increased proliferation, metastasis formation and poor prognosis 13,14 (Table I). Consistently, double transgenic mice overexpressing both p130CAS and ERBB2 in the mammary gland show an accelerated onset of tumour formation, providing evidence that p130CAS and the ERBB2 oncogene synergise in vivo to transform the mammary epithelium 13 (Table II). Indeed p130CAS silencing in ERBB2 transformed breast cancer cells is sufficient to inhibit tumour growth in vivo, and correlates with downregulation of proliferative and survival pathways, such as SRC and AKT activation, focal adhesion kinase (FAK) phosphorylation and CYCLIN D1 expression 11 .…”

Functional identification of genes causing estrogen independence of human breast cancer cells

“…High phospho-AKT and low AKT2 levels have been found associated with reduced survival of adjuvant tamoxifen-treated breast cancer patients [42]. We have demonstrated that BCAR1 protein levels are prognostic for disease recurrence and predictive for response to tamoxifen treatment [43][44][45], and BCAR1 also may be associated with HER2-Neu driven tumorigenesis [46,47]. GRB7 belongs to the 21 gene set (Oncotype DX assay) for breast cancer prognosis prediction and is often co-amplified with ERBB2 in breast cancer [9,29] and may contribute to the transformed cell phenotype [48].…”