The Pathogenesis of GPCR-positive Breast CancerLee, Jia-Ying (2019) The Pathogenesis of GPCR-positive Breast Cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractBreast cancer is a heterogeneous disease with a variety of molecular drivers regulating its growth, survival and response to therapy. We have identified aberrant overexpression of the type I angiotensin II receptor (AGTR1), a G-protein-coupled receptor (GPCR), in a subset of luminal breast cancers (characterized as ER+, PR+, HER-). Previously we found that Ang II, the ligand of AGTR1, stimulates the pro-inflammatory and pro-survival NF-κB transcription factor in vascular cells via activation of the CBM signalosome, a multi-protein complex consisting of three components: CARMA3, Bcl10 and MALT1. We have now demonstrated that the CBM signalosome similarly mediates NF-κB activation and promotes aggressive phenotypes in AGTR1-positive breast cancer. Unexpectedly, overexpression of AGTR1 in the luminal ZR75-1 cell line (ZR75-AGTR1) caused epithelial-to-mesenchymal transition (EMT), identified by the conversion to mesenchymal morphology, downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal markers N-cadherin, vimentin, as well as EMT transcription factors Snail and ZEB1. BT549, a breast cancer cell endogenously overexpressing AGTR1, also displays these mesenchymal characteristics. In BT549 cells, AGTR1 knockdown with siRNA and MALT1 knockdown with siRNA or shRNAs all reversed the expression of Snail. Moreover, disrupting MALT1 function in BT549 cells with siRNA or MALT1 protease inhibitors abrogated the migratory and invasive properties of these cells. The protease-activated receptor 1 (PAR1) is another GPCR utilizing the CBM signalosome as downstream signaling mediator. We found that overexpression of PAR1 in MCF7 cell also resulted in EMT-like morphological changes, downregulation of E-cadherin, and upregulation of vimentin, Snail and ZEB1. In MDA-MB-231 cells, which endogenously overexpress PAR1, knocking down PAR1 with siRNA or knocking down MALT1 with siRNA or shRNAs led to reversal of Snail. Disrupting MALT1 function in MDA-MB-231 cells with siRNA or MALT1 protease inhibitors abrogated the cell migratory and invasive ability of these cells. Importantly, gene set enrichment assay (GSEA) shows that MALT1 is strongly associated with EMT in human breast cancers and that EMT is one of the most dramatically induced pathways in AGTR1 or PAR1-positive triple-negative breast cancer. These results suggest that the CBM signalosome plays an important role in EMT in breast cancers harboring AGTR1 or PAR1 overexpression. Share
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