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

ABSTRACT: 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 ? (PPAR?) signaling. Furthermore, pharmacological activation of PPAR? 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.

SUBMITTER: Furth N

PROVIDER: S-EPMC6238411 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Furth Noa N Pateras Ioannis S IS Rotkopf Ron R Vlachou Vassiliki V Rivkin Irina I Schmitt Ina I Bakaev Deborah D Gershoni Anat A Ainbinder Elena E Leshkowitz Dena D Johnson Randy L RL Gorgoulis Vassilis G VG Oren Moshe M Aylon Yael Y

Life science alliance 20181030 5

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, ...[more]

PMID: 30456386

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Project description:BackgroundMany studies have found that large tumor suppressor kinase 1 (LATS1) and LATS2 play important roles in many diseases, but studies have been rare on the relationship between these genes and non-cardia gastric cancer (GC). We performed a case-control association study to investigate the associations between single nucleotide polymorphisms (SNPs) in LATS1 and LATS2 genes and Helicobacter pylori (H. pylori) infection as well as the risk of non-cardia GC.MethodsFirst, H. pylori infection was determined by the serological test using enzyme-linked immunoassay. Then genotyping of SNPs was performed for 808 samples by the Taqman method. Finally, unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age and gender, for the association of each SNP with the infection of H. pylori, the risk of non-cardia gastric cancer, as well as the expression of LATS1 and LATS2 proteins in non-cardia GC tissues, using the codominant, dominant, recessive, overdominant, and log-additive inheritance models, respectively.ResultsThe statistical results showed that LATS2 rs9552315 was associated with H. pylori infection, and the CC + CT genotype could reduce the risk of H. pylori infection (odds ratio [OR]: 0.549, 95% confidence interval [CI]: 0.339-0.881, P < 0.05) compared with the TT genotype in a dominant model. LATS1 rs9393175 was associated with the risk of non-cardia GC, and the AG genotype reduced the risk of non-cardia GC (OR: 0.702, 95% CI: 0.516-0.952, P < 0.05) compared with the GG + AA genotype in an overdominant model. LATS2 rs9509492 was associated with the risk of GC in an log-additive model. No associations were found between five SNPs and expression of LATS1 and LATS2 proteins in non-cardia GC tissue.ConclusionsLATS2 rs9552315 CT genotype may be a protective factor against infection of H. pylori. LATS1 rs9393175 AG genotype and LATS2 rs9509492 GG genotype may be protective factors for non-cardia GC.

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

Publications

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

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