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

Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or 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 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 PPARg signaling. Furthermore, pharmacological activation of PPARg 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 anti-cancer treatments. RNA from ZR75-1 and MCF7 transfected with siControl, siLATS1 or siLATS2 oligonucleotides was isolated and subjected to RNA-seq as above. For ZR75-1, three independent biological replicates were used. For MCF7, two independent biological replicates were used. ZR75-1 were transfected with either GFP only, GFP-LATS1 or GFP-LATS2. GFP-positive cells were sorted by FACS 24h following transfection (~80000 cells per sample). Two independent replicates were used.