Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

Abstract

G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases.

Keywords: ACE; AGTR1; Breast cancer; GPCR; Metastases.

Fig. 1

Major AGTR1 signalling pathways linked to cancer cell proliferation, angiogenesis and EMT. AngII activated AGTR1 recruits a CARMA3-Bcl10-MALT1 (CBM) signalosome, which activates NFκB downstream signalling. CARMA3 protein might act as a scaffold in recruiting Bcl 10, MALT 1 and IKKγ, the regulatory subunit of the IKK complex. Wherein MALT1 plays a key role in stimulating IKK activity by K63 linked polyubiquitination utilizing IKKγ as a substrate. The activation of this pathway leads to cell proliferation, survival and migration. AngII activation of AGTR1 also leads to EGFR transactivation via ROS‐ dependent Src kinase activation, phosphorylating EGFR and the adaptor proteins GRB2 and SHC, resulting in prolonged EGFR–ERK signalling. Continuous Ang II stimulation may direct alterations in the gene expression and induce phenotypic change from epithelial-to-mesenchymal transition (EMT).