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. Extracellular matrix (ECM) has been shown to mediate signaling through its receptors such as ?1 integrin and is critical to maintenance of normal tissue structure, a feature that is fundamentally disrupted in the malignant phenotype. ??1 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 ?1 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 lrECM). My initial studies have shown that ?1 integrin inhibition resulted in enhanced apoptosis and decreased proliferation among breast cancer cell lines in the 3D lrECM culture model and in vivo with no discernible toxicity to animals. Importantly, in a study of early stage invasive breast cancer patients, we found that increased ?1 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 ?1 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 ?1 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 ?1 integrin signaling mediates a survival signal via Akt using 3D lrECM culture models of invasive breast cancer and ductal carcinoma in situ (DCIS) and to expand upon the Akt-mediated survival effects of ?1 integrin signaling post-IR in the context of the tumor microenvironment in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Lawrence Berkeley National Laboratory
Organized Research Units
United States
Zip Code
Park, Catherine C; Georgescu, Walter; Polyzos, Aris et al. (2013) Rapid and automated multidimensional fluorescence microscopy profiling of 3D human breast cultures. Integr Biol (Camb) 5:681-91
Ahmed, Kazi Mokim; Zhang, Hui; Park, Catherine C (2013) NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells. Cancer Res 73:3737-48
Nam, Jin-Min; Ahmed, Kazi M; Costes, Sylvain et al. (2013) β1-Integrin via NF-κB signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancer. Breast Cancer Res 15:R60
Carbonell, W Shawn; DeLay, Michael; Jahangiri, Arman et al. (2013) β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res 73:3145-54
Nabavizadeh, Nima; Klifa, Catherine; Newitt, David et al. (2011) Topographic enhancement mapping of the cancer-associated breast stroma using breast MRI. Integr Biol (Camb) 3:490-6
Huang, Catherine; Park, Catherine C; Hilsenbeck, Susan G et al. (2011) β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res 13:R84
Weigelt, Britta; Lo, Alvin T; Park, Catherine C et al. (2010) HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment. Breast Cancer Res Treat 122:35-43
Nam, Jin-Min; Onodera, Yasuhito; Bissell, Mina J et al. (2010) Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin alpha5beta1 and fibronectin. Cancer Res 70:5238-48