LATS1 and LATS2 Suppress Breast Cancer Progression by Maintaining p53 activity, Cell Identity and Metabolic state

Introduction:

Hippo signaling inhibits tumorigenesis by regulating proliferation, differentiation and epithelial–mesenchymal transition (EMT). At the core of the Hippo pathway are the LATS1/2 (LATS) tumor suppressors, which inhibit the downstream effectors YAP and TAZ. Beyond their function in Hippo signaling, LATS kinases engage in cross-talk with the tumor suppressor p53.

Material and methods:

Bioinformatic analysis (TCGA), MMTV-PyMT mouse model, human IHC, gene expression analysis (RNA-seq), metabolic analysis (Sea Horse).

Results and discussion:

We examined the consequences of downregulation of LATS1 and LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerates mammary tumorigenesis in mice. Together, LATS function to maintain p53 in a tumor suppressive conformation. However, LATS1 and LATS2 also exert distinct impacts on breast cancer. LATS2 depletion in luminal B tumors results in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicits LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augments 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 common and distinct roles in protection against breast cancer.

Conclusion:

LATS-compromised tumors may harbor wild-type p53 with reduced tumor suppressive function (“pseudomutant p53”). Reduced expression of LATS1 or LATS2 in breast cancer may rewire distinct signaling networks resulting in differential susceptibilities to anti-cancer treatments.