GSE196555
Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas
Basal breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal-like plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Notably, transcriptional analyses of LATS1/2-deleted mammary epithelial cells revealed a gene expression program that associates with human basal breast cancers. Our study demonstrates in vivo roles for the LATS1/2 kinases in mammary epithelial homeostasis and luminal-basal fate control and implicates signaling networks induced upon the loss of LATS1/2 activity in the development of basal breast cancers. Overall design: Lineage-traced mammary cells from control (lsl-EYFP; K8CreERT2), LATS1/2-KO (LATS1/2f/f; lsl-EYFP; K8CreERT2), and LATS1/2-Sox9-KO (LATS1/2f/f; Sox9f/f; lsl-EYFP; K8CreERT2) mice were isolated and transcriptionally profiled. Each condition had three replicates.