Mammary carcinoma and angiogenesis: study of the role of HER2 in relation to tumor angiogenesis process and to the sensitivity to anti-tumoral drugs

Despite the correlation between HER2 expression and tumor angiogenesis, anti-angiogenesis drugs failed to reach sufficient efficacy in patients to be approved for HER2-positive breast cancer. About half of HER2-positive breast cancer presents an alternative splicing isoform called ?16. Tumors developed on mouse models transgenic for one or both isoforms of HER2 have different aspects, and angiogenesis seems to occur in different ways. In this way, HER2 and ?16 seem to drive different angiogenic phenotypes. Therefore, the aim of this thesis was to better analyze the role of the two isoforms in determining different patterns of vascularization. The different vascularization has been put in relation to the different effects of anti-angiogenic and anti-HER2 drugs. This study has been performed through histological, functional and molecular analysis of the tumors. The analysis of the vascularization in F1 tumors, in which one isoform or both can be expressed, revealed that the presence of HER2 is crucial for the establishment of the FVBhuHER2-like phenotype. The dominant role of full-length HER2 in tumor angiogenesis has been confirmed in a dynamic in vivo model of modulation of the expression of this isoform. HER2 isoforms have been found to have a crucial role in tumor angiogenesis. The dominant behavior of full-length HER2 affects the regularity of the vascular pattern, determining a vasculature that is less permeable to drugs and therefore less sensitive to anti-angiogenic and targeted agents. A molecular profile with more genes involved in sprouting angiogenesis suggests the need to further study the role of full-length HER2 in tumor vascularization, to find new targets to improve the pharmacological response to therapies.