ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness.

Overexpression of the ErbB2/HER2 receptor tyrosine kinase occurs in up to 20% of human breast cancers and correlates with aggressive disease. Several efficacious targeted therapies, including antibodies and kinase inhibitors, have been developed but the occurring of resistance to these agents is often observed. New therapeutic agents targeting the endocytic recycling and intracellular trafficking of membrane in tumor cells overexpressing ErbB2 are actually in clinical development. Nevertheless the mechanisms underlying ErbB2 downregulation are still obscure. We have previously demonstrated that the overexpression of the p130Cas adaptor protein in ErbB2 positive breast cancer, promotes tumor aggressiveness and progression. Here we demonstrate that lowering p130Cas expression in breast cancer cells is sufficient to induce ErbB2 degradation by autophagy. Conversely, p130Cas overexpression protects ErbB2 from degradation by autophagy. Furthermore, this autophagy-dependent preferential degradation of ErbB2 in absence of p130Cas is due to an increased ErbB2 ubiquitination. Indeed, the overexpression of p130Cas impairs ErbB2 ubiquitination by inhibiting the binding of Cbl and CHIP E3 ligases to ErbB2. Finally, our results indicate that p130Cas-dependent ErbB2 protection from degradation by autophagy may alter the sensitivity to the humanized monoclonal antibody trastuzumab. Consistently, in human ErbB2 positive breast cancers that develop resistance to trastuzumab, p130Cas expression is significantly increased suggesting that elevated levels of p130Cas can be involved in trastuzumab resistance.

Backgroundp130 Crk-associated substrate (p130CAS; also known as BCAR1) is a scaffold protein that modulates many essential cellular processes such as cell adhesion, proliferation, survival, cell migration, and intracellular signaling. p130Cas has been shown to be highly expressed in a variety of human cancers of epithelial origin. However, few data are available regarding the role of p130Cas during normal epithelial development and homeostasis.MethodsTo this end, we have generated a genetically modified mouse in which p130Cas protein was specifically ablated in the epidermal tissue.ResultsBy using this murine model, we show that p130Cas loss results in increased cell proliferation and reduction of cell adhesion to extracellular matrix. In addition, epidermal deletion of p130Cas protein leads to premature expression of “late” epidermal differentiation markers, altered membrane E-cadherin/catenin proteins localization and aberrant tyrosine phosphorylation of E-cadherin/catenin complexes. Interestingly, these alterations in adhesive properties in absence of p130Cas correlate with abnormalities in progenitor cells balance resulting in the amplification of a more committed cell population.ConclusionAltogether, these results provide evidence that p130Cas is an important regulator of epidermal cell fate and homeostasis.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0289-z) contains supplementary material, which is available to authorized users.

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The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15–20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enhancing tumorigenesis. Therefore, inhibiting p130Cas/ErbB2 interaction might represent a new therapeutic strategy to target breast cancer. Here we demonstrate by performing Molecular Modeling, Molecular Dynamics, dot blot, ELISA and fluorescence quenching experiments, that p130Cas binds directly to ErbB2. Then, by structure-based virtual screening, we identified two potential inhibitors of p130Cas/ErbB2 interaction. Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ErbB2 binding and significantly affect cell proliferation and sensitivity to Trastuzumab. Overall, this study identifies p130Cas/ErbB2 complex as a potential breast cancer target revealing new therapeutic perspectives for protein-protein interaction (PPI).