MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.

Autor:	Lee JL; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Ekambaram P; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Carleton NM; Women's Cancer Research Center, Magee-Women's Research Institute, Pittsburgh, Pennsylvania.; Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Hu D; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Klei LR; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Cai Z; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; School of Medicine, Tsinghua University, Beijing, China., Myers MI; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Hubel NE; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Covic L; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts., Agnihotri S; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Krappmann D; Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz-Zentrum München, Neuherberg, Germany., Bornancin F; Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland., Lee AV; Women's Cancer Research Center, Magee-Women's Research Institute, Pittsburgh, Pennsylvania.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Oesterreich S; Women's Cancer Research Center, Magee-Women's Research Institute, Pittsburgh, Pennsylvania.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., McAllister-Lucas LM; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Lucas PC; Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2022 Mar 01; Vol. 20 (3), pp. 373-386.
DOI:	10.1158/1541-7786.MCR-21-0208
Abstrakt:	MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. Implications: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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