BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the Hippo pathway component TAZ

Abstract

Since the metastatic progression of cancers is often fatal with limited treatment options, understanding the mechanism of metastasis is imperative for designing novel and targeted therapies. TAZ has been identified as a novel oncogene in both breast and lung cancers and is inhibited by the Hippo signaling pathway. In this study we provide convincing evidence that overexpression of TAZ in a mammary epithelial cell line, MCF10A, leads to enhanced cell migration - a fundamental characteristic of the metastatic progression of cancers. In addition, we identified the secreted growth factor BMP4 as a mediator of TAZ-induced cell migration. TAZ induces BMP4 transcription through the TEAD family of transcription factors, which mediate BMP4 promoter activation through binding to TEAD response element 1 (TRE1). Importantly, BMP4 activation by TAZ also enhances signaling downstream of TAZ, in particular, promoting Smad1/5 intracellular signaling. Functionally, short hairpin RNA-mediated knockdown of BMP4 rescued TAZ-induced cell migration. Our findings have identified a novel TAZ/TEAD/BMP4 signaling axis responsible for cell migration, with future implications in the development of targeted therapeutics for metastatic breast cancers.