Inactivation of LATS1/2 Drives Luminal-Basal Plasticity To Initiate Basal-Like Mammary Carcinomas

Authors

Joseph G Kern
Andrew M Tilston-Lunel
Anthony Federico
Boting Ning
Amy Mueller
Grace B Peppler
Eleni Stampouloglou
Nan Cheng
Randy L Johnson
Marc E Lenburg
Jennifer E Beane
Stefano Monti
Xaralabos Varelas

Publication Date

11-28-2022

Journal

Nature Communications

Abstract

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal 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 Krt14 and Sox9-expressing 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. Gene expression analyses of LATS1/2-deleted mammary epithelial cells notably revealed a transcriptional program that associates with human basal-like 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-like breast cancer.

Keywords

Humans, Animals, Mice, Protein Serine-Threonine Kinases, Genes, Regulator, Signal Transduction, Carcinoma, Epithelial Cells, Tumor Suppressor Proteins

Comments

Supplementary Materials

PMID: 36443313