Development of Preclinical Models of Mammary Carcinogenesis: Functional Role of Her2 and its Isoforms in Tumor Progression and in Drug Resistance

Overexpression of huHER2 occurs in nearly 15†"20% of breast cancers, and it is generally associated with poor patient survival. Existing therapies such as trastuzumab and lapatinib are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Elucidation of the molecular mechanisms underlying resistance is leading to the identification of therapies and strategies to manage resistance to HER2-targeted therapies. In addition to intrinsic and acquired resistance associated to HER2 oncogene, the induction of bypass pathways that reactivate growth factor-dependent signalling upon oncogene inhibition is likely pervasive across cancers and should be anticipated. Together, these findings underscore that many resistance mechanisms fall into predictable and therapeutically tractable themes, and can be effectively targeted with rationally designed combined therapies. It is, therefore, necessary to come back to dissect HER2 pathway and unravel key features contributing to its transforming capacity. The present thesis, is focused on the role played by HER2-loss variants and Delta16 isoform in mediating HER2 oncogenic activity and in conditioning the response to HER2 therapies in breast cancer. These HER2 phenotypes can drive differential drug responses of the tumor and of distant metastases. Thus, recent investigations on drug resistance and on tumor biology converged to the development of preclinical cancer models representative of cancer heterogeneity and able to mimic all possible scenarios observed in human tumors. In this project, thanks to the availability of several preclinical models representative of HER2 postive breast cancer, it was studied the contribute of HER2 and of its variants to cancer development and drug resistance. In addition, with the purpose of obtaining preclinical models that could best recapitulate human tumor heterogeneity a panel of breast cancer PDX was developed.