Role Of d16HER2 Splice Variant In Breast Cancer Stem Cells

Castagnoli, Lorenzo (2018). Role Of d16HER2 Splice Variant In Breast Cancer Stem Cells. PhD thesis The Open University.



The transmembrane tyrosine kinase receptor HER2 is overexpressed in about 20% of human breast cancers (BCs). Evidence suggests that the co-existence of the full-length/wild-type HER2 oncoprotein (WTHER2) with its altered isoforms increases the heterogeneity of HER2 overexpressing (HER2+) disease thus affecting its biology and treatment response. We found that ~90% of HER2+ BC patients express a WTHER2 isoform characterized by the lack of exon 16 (d16HER2), a peculiar absence promoting the generation of stable and constitutively activated HER2 homodimers. Since the impact of d16HER2 in HER2+ BC disease was debatable at the beginning of my Ph.D. project, I focused my studies to investigate and unravel d16HER2 implication in HER2+ BC aggressiveness, susceptibility to specific biotherapies and stemness. Our in vitro and in vivo findings made clearer the potent oncogenicity driven by d16HER2 variant vs WTHER2 unveiling its direct functional interplay with the activated tyrosine kinase SRC that was found to be coupled with d16HER2 expression/activity in HER2+ BCs. Further, pre-clinical and clinical data indicated that d16HER2 activation determines the greatest benefits from trastuzumab administration in HER2+ BCs. Additionally, our results pointed to a crucial d16HER2 role in the regulation of the BC stem cells (BCSCs) activity through its functional interaction with the NOTCH family members. We also observed that the higher trastuzumab efficiency inhibits the growth/progression of HER2+ BCs characterized by an activated d16HER2 signature was consistent with its ability to target BCSCs effectively. Finally, our data revealed that d16HER2 expression/activity in driving tumour aggressiveness could be extended also to HER2+ gastric cancers.

The results of my Ph.D. thesis contribute to highlight the crucial role played by d16HER2 in the aggressiveness, sensitivity to trastuzumab and stemness of HER2+ BCs vs the WTHER2 receptor.

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