Abstract P2-05-01: Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas

Abstract

Abstract Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells but undergo plasticity to a basal-like state upon transformation. Identifying cellular mechanisms underlying this luminal-basal plasticity will allow an improved understanding of the pathogenesis of basal-like breast cancers. The Hippo signaling pathway, an important cell fate regulator across many tissues, has been implicated in breast cancer development. Central to Hippo signaling are the tumor suppressor kinases LATS1 and LATS2 (LATS1/2), which function to inhibit the transcriptional regulators YAP and TAZ (YAP/TAZ). In this study, we investigated the roles of LATS1/2 in the maintenance of mammary epithelial homeostasis and tumorigenesis in vivo. Using genetic mouse models, we found that conditional co-deletion of LATS1/2 in adult luminal cells promotes rapid proliferation and acquisition of basal cell traits, leading to early development of basal-like ductal carcinoma in situ and an eventual transition to a metastatic state. Further co-deletion experiments demonstrated that these phenotypes are dependent on YAP/TAZ. Transcriptional analyses of LATS1/2-null cells sorted from mammary glands demonstrated that these cells adopt gene expression signatures that correlate with mammary basal cells and human basal-like breast cancers, and revealed an association with Sox9, a transcription factor implicated in luminal progenitor fate and basal-like carcinomas. Collectively, this study demonstrates that LATS1/2 are important mediators of luminal cell fate in mammary epithelial homeostasis and that dysregulation of Hippo signaling in vivo promotes luminal-basal cell plasticity leading to basal-like mammary carcinoma development. Citation Format: Joseph Kern, Andrew Tilston-Lunel, Anthony Federico, Boting Ning, Grace Peppler, Eleni Stampouloglou, Marc Lenburg, Jennifer Beane, Stefano Monti, Xaralabos Varelas. Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-05-01.