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

DOI Web Site 1 Citations
  • Noa Furth
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Ioannis S Pateras
    Laboratory of Histology and Embryology Medical School, University of Athens, Athens, Greece
  • Ron Rotkopf
    Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel
  • Vassiliki Vlachou
    Laboratory of Histology and Embryology Medical School, University of Athens, Athens, Greece
  • Irina Rivkin
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Ina Schmitt
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Deborah Bakaev
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Anat Gershoni
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Elena Ainbinder
    Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel
  • Dena Leshkowitz
    Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel
  • Randy L Johnson
    Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Vassilis G Gorgoulis
    Laboratory of Histology and Embryology Medical School, University of Athens, Athens, Greece
  • Moshe Oren
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Yael Aylon
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Description

<jats:p>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.</jats:p>

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