LATS1/2 inactivation in the mammary epithelium drives the evolution of a tumor-associated niche.

Abstract

Basal-like breast cancers exhibit distinct cellular heterogeneity that contributes to disease pathology. In this study we used a genetic mouse model of basal-like breast cancer driven by epithelial-specific inactivation of the Hippo pathway-regulating LATS1 and LATS2 kinases to elucidate epithelial-stromal interactions. We demonstrate that basal-like carcinoma initiation in this model is accompanied by the accumulation of distinct cancer-associated fibroblasts and macrophages and dramatic extracellular matrix remodeling, phenocopying the stromal diversity observed in human triple-negative breast tumors. Dysregulated epithelial-stromal signals were observed, including those mediated by TGF-β, PDGF, and CSF. Autonomous activation of the transcriptional effector TAZ was observed in LATS1/2-deleted cells along with non-autonomous activation within the evolving tumor niche. We further show that inhibition of the YAP/TAZ-associated TEAD family of transcription factors blocks the development of the carcinomas and associated microenvironment. These observations demonstrate that carcinomas resulting from Hippo pathway dysregulation in the mammary epithelium are sufficient to drive cellular events that promote a basal-like tumor-associated niche and suggest that targeting dysregulated YAP/TAZ-TEAD activity may offer a therapeutic opportunity for basal-like mammary tumors.