The CARMA3–Bcl10–MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor–Positive Breast Cancer

Abstract

The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1 breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NFκB signaling pathways to improve the treatment of this breast cancer subset. These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. .

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

“…Interestingly, these two subsets show abnormal expressions of AGTR1 or HER2 in a mutually exclusive manner (128). In AGTR1 and HER2 positive breast cancer cell lines, NF-κB is activated upon stimulation with Angiotensin II or the HER2 ligand heregulin, respectively, in a CARMA3-dependent manner (18, 128, 129).…”

Caspase recruitment domain family member 10 regulates carbamoyl phosphate synthase 1 and promotes cancer growth in bladder cancer cells

“…And knockdown of CARD10 suppressed bladder tumour cell (UMUC3 and T24) proliferation and promoted apoptosis, thus we supposed CARD10 might act as an oncogene in bladder cancer . CARD10 plays a critical role in intracellular signalling transduction and impacts many oncologic processes in tumour proliferation, metastasis, angiogenesis, and stemness and chemotherapeutic resistance . These characteristics may render it a therapeutic target.…”

“…12,18 CARD10 plays a critical role in intracellular signalling transduction and impacts many oncologic processes in tumour proliferation, metastasis, angiogenesis, and stemness and chemotherapeutic resistance. [19][20][21] These characteristics may render it a therapeutic target. In this study, we focused on the downstream effect of CARD10 on tumour growth in bladder cancer.…”

Targeting AGTR1/NF-κB /CXCR4 axis by miR-155 attenuates oncogenesis in Glioblastoma

“…1c), implicating an association between elevated AGTR1 levels with poor survival of the clinically advanced GBM patients. Several independent studies implicated AGTR1 upregulation in cell proliferation, invasion and distant metastases in multiple malignancies [7,13,17]. Therefore, to ascertain the role of AGTR1 in GBM oncogenesis, we performed stable shRNA-mediated knockdown of AGTR1 in SNB19 cells, an AGTR1-positive GBM cell line ( Fig.…”

“…One of the mechanisms for AGTR1-mediated tumorigenesis has been attributed to multiple signaling pathways downstream of AGTR1, for instance, nuclear factor-κB (NF-κB) signaling in BCa [17]. Moreover, angiotensin II (ATII), the ligand of AGTR1 is known to activate NF-κB signaling downstream of AGTR1 in endothelial and vascular smooth muscle cells [18].…”