LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state

• Published in: Life science alliance 2018-10, Vol.1 (5), p.e201800171-e201800171
• Main Authors: Furth, Noa, Pateras, Ioannis S, Rotkopf, Ron, Vlachou, Vassiliki, Rivkin, Irina, Schmitt, Ina, Bakaev, Deborah, Gershoni, Anat, Ainbinder, Elena, Leshkowitz, Dena, Johnson, Randy L, Gorgoulis, Vassilis G, Oren, Moshe, Aylon, Yael
• Format: Article
• Language: English
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.201800171

Deregulated activity of LArge Tumor Suppressor (LATS) tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of down-regulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs was significantly down-regulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced peroxisome proliferator-activated receptor γ (PPARγ) signaling. Furthermore, pharmacological activation of PPARγ elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anticancer treatments.