p130Cas scaffold protein regulates ErbB2 stability by altering breast cancer cell sensitivity to autophagy

Abstract

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.

Modeling ErbB2-p130Cas interaction to design new potential anticancer agents

“…The mechanism through which p130Cas mediates resistance to Trastuzumab might rely on the increased ErbB2 stability to the cell membrane. This increased stabilization of ErbB2 by p130Cas might be the crucial event driving breast cancer progression and resistance, strengthening the relevance of p130Cas as putative therapeutic target to overcome resistance to Trastuzumab 5 .…”

“…Among them, Trastuzumab was approved for the treatment of breast cancers overexpressing ErbB2, alone or in combination with standard chemotherapy. The mechanism of action of Trastuzumab is complex and not well understood, resulting in modest downregulation of the ErbB2 receptor 4,5 .…”

“…Recently, it was reported that p130Cas is able to stabilize ErbB2, by binding and protecting it from autophagic degradation. Indeed, p130Cas binding to ErbB2 does not allow the association of CHIP and Cbl, the major E3 ubiquitin ligases binding ErbB2, possibly through steric hindrance 5 .…”

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

“…In this context, it has been shown that Hsp90 inhibition can induce ErbB2 ubiquitination followed by its downregulation [52], however the mechanisms underlying ErbB2 downregulation are still obscure. Recently it has been demonstrated that molecular association between p130Cas and ErbB2 protects the receptor from degradation through autophagy [53]. On this regard, increasing evidence points out that ubiquitination is an important mechanism driving autophagic degradation.…”

“…On this regard, increasing evidence points out that ubiquitination is an important mechanism driving autophagic degradation. Interestingly, in breast cancer cells overexpressing ErbB2, p130Cas protects ErbB2 from autophagy-mediated degradation by interfering with its ubiquitination, thus suggesting that high levels of p130Cas expression might be crucial to promote resistance to trastuzumab treatment by protecting ErbB2 from degradation [53].…”