Integrin α3β1 as a breast cancer target

Abstract

Introduction: Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells.

Areas covered: Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer.

Expert opinion: Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells.

Figure 1

Some studies have shown that association of integrin α3β1 with the tetraspanin protein CD151 can regulate its binding affinity for laminin ligands present in the extracellular matrix (ECM) and contribute to subsequent signaling functions. However, other studies have identified functions of the CD151:α3β1 complex that appear independent of integrin-ECM binding. Interestingly, FAK has been shown to be activated by both the CD151:α3β1 complex, and binding of α3β1 to ECM, suggesting that some pro-tumorigenic functions of α3β1 may occur via FAK/Src-to-MAPK signaling pathways, as depicted (see text and references [16,17] for details). As indicated by the question mark (?), the full extent of functional interactions between ECM-bound α3β1 and CD151-bound α3β1 is not yet clear, which leaves open the possibility that there may be functionally distinct pools of α3β1 within the same cell. Other membrane bound proteins have also been shown to interact laterally with α3β1, leading to both ‘outside-in’ and ‘inside-out’ signaling events (see text for details).

Figure 2

The ability of α3β1 on breast cancer cells to promote expression of MMP-9, Cox-2, and possibly other genes that mediate ECM remodeling and/or crosstalk to endothelial cells points towards an important role for this integrin in regulating the ability of the cancer cell to alter the tumor microenvironment in ways that promote angiogenesis and malignant growth.

Figure 3

Recent findings indicate that integrin α3β1 can regulate the expression of multiple genes in breast cancer cells (designated schematically as A–G), some of which have been implicated in different aspects of tumor growth, invasion, and/or the angiogenic switch, which suggests that antagonists of α3β1 function might produce the effect of a combinatorial strategy. ECM, extracellular matrix.