TY - JOUR
T1 - LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state
AU - Furth, Noa
AU - Pateras, Ioannis S.
AU - Rotkopf, Ron
AU - Vlachou, Vassiliki
AU - Rivkin, Irina
AU - Schmitt, Ina
AU - Bakaev, Deborah
AU - Gershoni, Anat
AU - Ainbinder, Elena
AU - Leshkowitz, Dena
AU - Johnson, Randy L.
AU - Gorgoulis, Vassilis G.
AU - Oren, Moshe
AU - Aylon, Yael
N1 - Funding Information:
We thank Giuseppe Mallel for fruitful discussions and valuable inputs; Sima Benjamin, Dana Robbins, Orit Zion, and Shlomit Gilad (Israel National Center for Personalized Medicine, Weizmann Institute of Science [WIS]) for their help with RNA-seq; Gil Stelzer (Life Sciences Core Facilities, WIS) for assisting with pipeline analysis of human cell line RNA-seq results; Ori Brenner (Veterinary Resources, WIS) for help with histological analysis; and Ziv Porath (Life Sciences Core Facilities, Faculty of Biochemistry, WIS) for ImageStream data acquisition and analysis. We thank James Martin (Baylor College of Medicine, Houston, TX, USA) for the generous sharing of conditional knockout mice. This work was supported by grants from the Rising Tide Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a Center of Excellence grant from the Israel Science Foundation, the Comisaroff Family Trust, the Estate of John Hunter, and the Moross Integrated Cancer Center. M Oren is incumbent of the Andre Lwoff chair in molecular biology.
Publisher Copyright:
© 2018 Furth et al.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
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U2 - 10.26508/lsa.201800171
DO - 10.26508/lsa.201800171
M3 - Article
C2 - 30456386
AN - SCOPUS:85057055841
SN - 2575-1077
VL - 1
JO - Life science alliance
JF - Life science alliance
IS - 5
M1 - e201800171
ER -