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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.
Highlights
Molecular and clinical studies indicate that ErbB2 has important implications in tumor etiology and progression
Within 48 hours, p130Cas expression was effectively silenced by about 80% compared to cells infected with scramble sequences, while p130Cas overexpression resulted in about 30–40% increase of protein expression compared to control infected cells (Figure 1A)
Since CHIP and Cbl E3 ligases have been reported to associate with ErbB2 and to mediate its ubiquitination [29,30,31] and we have previously demonstrated that p130Cas immunoprecipitates with ErbB2 ([15] and Supplementary Figure 5), we tested whether the observed differences of
Summary
Molecular and clinical studies indicate that ErbB2 has important implications in tumor etiology and progression. Overexpression of ErbB2 (Her2/Neu), is involved in the pathogenesis of nearly 20–30% of invasive breast cancers and is associated with an aggressive phenotype. ErbB2 overexpression identifies patients who are likely to respond to therapy with trastuzumab, not all patients benefit from treatment. 15% of patients relapse after therapy due to de novo or acquired resistance [1,2,3]. Intense investigations are necessary to understand the factors that contribute to the resistance and to identify therapeutic strategies to overcome the resistance. Several mechanisms have been proposed for the acquirement of resistance including the poor internalization of ErbB2 resulting in a long half-life at the plasma membrane [4,5,6,7]. It has been shown that Hsp inhibition can induce ErbB2 ubiquitination followed by its downregulation [8, 9], the mechanisms underlying ErbB2 downregulation are still obscure
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