Crosstalk between YAP and HER2 drives HER2-mediated breast cancer progression via synergistic growth factor upregulation

Breast cancer is the most frequently diagnosed cancer worldwide, with the HER2-positive subtype accounting for ~ 25% of cases. In this study, we examine the role of oncogene YAP in HER2-positive breast cancer progression and YAP as a potential therapeutic target in combination with HER2-targeted therapy. We studied expression of YAP in 76 HER2-positive patients, high expression of YAP was strongly associated with aggressive disease that was treatment resistant and had poor disease-free survival outcomes. To understand the underlying mechanism of YAP in aggressive subset of HER2-positive subtype, we established MCF10a cell line co-expressing HER2 and YAP. YAP co-expression synergistically enhanced HER2-mediated proliferation and migration in the absence of growth factors. Transcriptional profiling of co-expressing cell lines revealed concomitant synergistic upregulation of growth factors expression. Conversely, YAP knockdown in HER2 overexpression background mitigated HER2-mediated proliferation and migration and downregulated growth factor expression. A significant number of growth factors were represented in the YAP and HER2 co-regulated target genes. We tested the effect of the co-treatment of YAP and HER2-targeted drugs on HER2-positive breast cancer cell lines, SKBR3 and ZR75-1. The combination treatment of Trastazumab with Verteporfin showed synthetic lethality with significant inhibition of cell growth comparted to individual drug treatment with concomitant and significant downregulation of growth factors expression, confirming role of co-regulated growth factor expression by YAP with HER2. The study provides proof-of-principal for potential use of YAP-targeting drugs in combination with anti-HER2 therapy for aggressive subset of HER2-positive subtype of breast cancer.