The Prognostic Value of BCAR1 in Patients with Primary Breast Cancer

Abstract

Purpose: BCAR1, the human homologue of the rat p130Cas protein, was identified in a functional screen for human breast cancer cell proliferation resistant to antiestrogen drugs. Here, we study the prognostic value of quantitative BCAR1 levels in a large series of breast cancer specimens.Experimental Design: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols. Tumor levels of BCAR1 were correlated with relapse-free survival (RFS) and overall survival (OS) and compared with collected data on urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1).Results: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein. BCAR1 levels exhibited a positive correlation with steroid hormone receptor levels, age and menopausal status, and uPA and PAI-1 levels. The level of BCAR1 (continuous or categorized as low, intermediate, or high) was inversely related with RFS and OS time. Multivariate analysis showed that BCAR1 levels contributed independently to a base model containing the traditional prognostic factors for both RFS and OS (both P < 0.0001).When added together with uPA and PAI-1 in the multivariate model, BCAR1 contributed independently of PAI-1 and was favored over uPA. Interaction tests allowed for additional analyses of BCAR1 protein levels in clinically relevant subgroups stratified by nodal and menopausal status.Conclusions: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1.

Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression

“…Crk is an adaptor protein that regulates cells spreading and migration by coupling critical signaling proteins such as EGFR, PDGFR, and C-Abl to the cytoskeleton and focal adhesions including the scaffolding protein p130Cas (47). p130Cas and its family members are necessary for cell migration and cancer cell invasion and have been associated with cancer progression in patients (48)(49)(50)(51). Interestingly, p130Cas coprecipitates with PEAK1 and PEAK1 modulates p130Cas-Y249 phosphorylation (Fig.…”

Integrin signalling adaptors: not only figurants in the cancer story

“…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 . In oestrogen receptor (ER)-positive human breast tumours, overexpression of p130CAS correlates with intrinsic resistance to tamoxifen treatment in a large subset of human breast cancer samples [15][16][17] .…”

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].…”