The breast cancer susceptibility FGFR2 provides an alternate mode of HER2 activation

Fibroblast growth factor receptor 2 (FGFR2) has been shown reproducibly in genome-wide association studies to be associated with increased breast cancer risk. Here we show that mouse mammary tumor virus-neu mice develop breast carcinomas with FGFR2 immunoreactivity that parallels HER2 expression. FGFR2 signaling promotes HER2 shedding through the metalloprotease ADAM10 leading to intracellular accumulation of the truncated p95HER2 protein. This is accompanied by enhanced HER2 signaling and diminished sensitivity to trastuzumab. Functionally, FGFR2 facilitates HER2-mediated cell proliferation, acinar growth in three-dimensional morphogenesis assays and promotes tumor progression in mouse xenografts. These data implicate FGFR2 in a novel mechanism of ErbB activation and demonstrate an important interaction between FGFR2 and HER2 in promoting breast cancer progression.Oncogene advance online publication, 2 February 2015; doi:10.1038/onc.2014.440.