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 This review covers studies from the past decade that implicate integrins as promising anti-cancer targets and discusses the development of integrin antagonists as anti-cancer therapeutics. In particular, this paper discusses recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target, and considers 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.

Integrin α3β1 controls mRNA splicing that determines cyclooxygenase-2 (Cox-2) mRNA stability in breast cancer cells

“…These findings have important implications for understanding how integrins, in particular a3b1, contribute to cancer progression through gene regulation that drives malignant cell behavior and tumor angiogenesis, and how this regulation might be exploited in therapeutic strategies to inhibit cancer progression. Indeed, both a3 and Cox-2 are expressed highly in human breast cancers (Morini et al, 2000;Singh-Ranger et al, 2008;Subbaram and DiPersio, 2011), and our data mining analysis revealed that both are correlated with disease progression in human breast cancer (supplementary material Fig. S1).…”

“…It is well known that Cox-2 plays important roles in driving tumor angiogenesis and breast cancer progression, and clinical investigations of breast and other cancers have indicated that treatment with Cox-2 inhibitors might improve survival in some cancer patients (Harris, 2009;Howe, 2007;Singh-Ranger et al, 2008). However, adverse side effects have been associated with direct inhibitors of Cox-2, and indirect suppression of Cox-2 through targeting of integrin a3b1, or its downstream effectors, might avoid these side effects (Subbaram and DiPersio, 2011). Therefore, further investigation of the pathways whereby a3b1 controls AEU and/ or suppresses NMD might lead to new therapeutic strategies to block these pathways in tumor cells; thereby reducing gene expression of Cox-2 (and other pro-cancer genes) through enhanced NMD and providing protective effects in breast cancer patients.…”

“…Preclinical studies have shown that a3b1 promotes malignant behavior of breast cancer cells in vivo and in vitro (Cagnet et al, 2013;Mitchell et al, 2010;Morini et al, 2000;Scales et al, 2013;Sugiura and Berditchevski, 1999;Wang et al, 2004), as well as skin tumorigenesis in vivo (Sachs et al, 2012), implicating this integrin as a potential therapeutic target to inhibit cancer progression and metastasis (Subbaram and DiPersio, 2011). Laminin-332, a major ECM ligand for a3b1, is often expressed highly in breast cancer cells, where it enhances motility (Carpenter et al, 2009;Carpenter et al, 2008).…”

Integrin Regulation of Epidermal Functions in Wounds

“…For example, the integrin-blocking agent Cilengitide, an RGD mimetic, has shown promise in clinical trials involving the treatment of recurrent glioma. 165,166 It is well known that wound healing and skin carcinogenesis share similarities regarding both epidermal cell function and microenvironmental factors that drive each process, 57 and integrin-targeting therapies are relevant to the treatment of chronic wounds for many of the same reasons that they are relevant to the treatment of cancer. For example, we have already discussed how roles for some integrins within the stem cell compartment may be important during both wound re-epithelialization and skin carcinogenesis (see Epidermal proliferation).…”

Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

“…Interactions between FN and integrins play an important role in tumor cell migration, invasion and metastasis (25). αvβ6 integrin was found to be significantly upregulated in certain cancer types including colon (18,26) and ovarian carcinoma (27) and in early stage non-small cell lung cancer (NSCLC) (28).…”