Historically, research has focused on the ability of ionizing radiation (IR) to eradicate the tumor by eliminating cancer cells through DNA damage and apoptosis. However, as we have pointed out in a recent review, the global consequences of IR on the normal tissue microenvironment can also have important clinical implications (Appendix I). Extracellular matrix (ECM) has been shown to mediate signaling through its receptors such as Beta1 integrin and is critical to maintenance of normal tissue structure, a feature that is fundamentally disrupted in the malignant phenotype. Beta1 integrin signaling has been implicated in breast cancer progression, and, in addition, has been shown to facilitate resistance to chemotherapy and IR in several human cancers. We have shown previously that Beta1 integrin expression is aberrantly up regulated after IR exposure in a heritable and persistent manner in mammary epithelial cells cultured in a 3- dimensional laminin rich matrix (3D IrECM), (Appendix II). My initial studies have shown that Beta1 integrin inhibition resulted in enhanced apoptosis and decreased proliferation among breast cancer cell lines in the 3D IrECM culture model and in vivo with no discernible toxicity to animals (Appendix III). Importantly, in a study of early stage invasive breast cancer patients, we found that increased Beta1 integrin expression was prognostic for recurrence-free and overall survival at 5 and 10 years (Appendix IV). In the present proposal, our preliminary data demonstrates that Beta1 integrin inhibition enhances the therapeutic efficacy of IR in 3DlrECM and in vivo;these promising findings have the potential to impact clinical RT for patients. We hypothesize that Beta1 integrin mediates a pro-survival signal after IR via Akt that can be targeted for therapy. The primary focus of this proposal therefore will be to investigate if IR induced Beta1 integrin signaling mediates a survival signal via Akt using 3D IrECM culture models of invasive breast cancer and ductal carcinoma in situ (DCIS) and to expand upon the Akt-mediated survival effects of Beta1 integrin signaling post-IR in the context of the tumor microenvironment in vivo.
In the present proposal, our preliminary data demonstrates that Beta1 integrin inhibition enhances the therapeutic efficacy of IR in 3DlrECM and in vivo;these promising findings have the potential to impact clinical RT for patients. We hypothesize that Beta1 integrin mediates a pro-survival signal after IR via Akt that can be targeted for therapy. The primary focus of this proposal therefore will be to investigate if IR induced Beta1 integrin signaling mediates a survival signal via Akt using 3D IrECM culture models of invasive breast cancer and ductal carcinoma in situ (DCIS) and to expand upon the Akt-mediated survival effects of Beta1 integrin signaling post-IR in the context of the tumor microenvironment in vivo.
