Targeting cell-extracellular matrix (ECM) interactions to enhance radiation efficacy for breast cancer treatment

Proc Amer Assoc Cancer Res, Volume 46, 2005 1659 Background: Cell interactions with the extracellular matrix (ECM) have been shown to affect radiation response in several malignant cell lines, including breast cancer. β1 integrin is a critical mediator of cell-ECM interactions and has been implicated in multiple stages of cancer progression. β1 integrin mediated signaling has been shown to enhance cancer cell survival following radiation (Cordes, 2002). We have previously shown that ionizing radiation (IR) induces persistent and heritable changes in β1 integrin expression and distribution in human mammary epithelial cells cultured in a 3-dimensional laminin-rich culture (3D-rBM). To investigate how β1 integrin signaling modifies radiation response in the context of normal mammary epithelial cells and malignant cells, we tested the ability of β1 integrin inhibitory monoclonal antibody, AIIB2, to modify radiation effects in culture and in vivo. Methods: To model normal and malignant breast cells in their physiologic microenvironment, we propagated both non-malignant and tumorigenic breast cells in 3D-rBM. Non-malignant S1 cells form organized acinar structures while tumorigenic cell lines, T4-2, MDA-MB-231 and MCF-7 form disorganized, invasive colonies. To disrupt cell-ECM signaling via β1 integrin, β1 integrin inhibitory antibody, AIIB2 was added to cultures alone or 24 hours prior to a single administration of ionizing radiation at doses from 0-8 Gy. Cultures were assayed 48-72 hours after treatment for proliferation (by presence of Ki-67 nuclear antigen) and apoptosis (by TUNEL). To test the effects of these treatments in vivo, T4-2 xenografts were established in adult female nu -/- mice and given AIIB2 alone or in combination with single fractions of ionizing radiation (0-8 Gy). Tumors were evaluated for growth and for proliferation and apoptosis ex-vivo. Results: Inhibition of β1 integrin with monoclonal AIIB2 in combination with ionizing radiation increased the cytostatic effect in malignant tumors in 3D-rBM compared to antibody alone. In contrast, there was little effect on non-malignant cell line, S-1 in culture. In vivo, the combination of AIIB2 and IR had an increased cytostatic effect on T4-2 xenografts compared to AIIB2 alone with minimal toxicity. Conclusions: Malignant breast cell colonies are susceptible to decreased growth and increased apoptosis with β1 integrin inhibitory antibody and IR. In contrast, β1 integrin signaling in the context of normal tissue organization is refractory to β1 integrin inhibition and IR. The combination of β1 integrin inhibition using monoclonal antibody AIIB2 enhances the therapeutic efficacy of IR in malignant breast cancer and has potential for therapeutic clinical applications.