Abstract P4-05-02: Role of the Atr Protein Kinase and Curcumin in Tumor-Stromal Interactions in Breast Cancer

Abstract

Abstract Carcinoma-associated fibroblasts (CAFs) play important roles in the genesis and thrive of various types of epithelial cancers, including breast carcinomas. Indeed, various genetic and epigenetic variations have been identified in stromal fibroblasts, and we have recently shown that CAFs as well as their corresponding counterparts (TCFs) display neoplastic-specific changes (Hawsawi et al., 2008). We have also shown that the levels of the tumor suppressor proteins p53 and p21 are down-regulated in CAFs as compared to TCFs. During the cellular response to DNA damage these genes are under the control of important proteins such as Atr, a protein kinase essential for the maintenance of genomic integrity. To further elucidate the molecular changes that occur in breast cancer-associated fibroblasts we assessed the expression of Atr and have shown that the level of the Atr protein kinase is lower in 7 out of 10 (70%) CAFs as compared to their corresponding TCFs. Using specific ATR-siRNA we have shown that ATR negatively controls the expression of various proteins involved in the stromal-epithelial interactions. These include the stromal cell-derived factor 1 (SDF1), the vascular endothelial growth factor (VEGF) and the matrix metalloproteinase-2 (MMP2). In addition, the ELISA assay was used to show that the level of these proteins was higher in the conditioned media from stromal fibroblasts expressing specific ATR-siRNA as compared to control cells. Importantly, serum-free conditioned media from ATR-defective cells stimulated the proliferation and invasion/migration of cultured human breast cancer cells in an SDF1-dependent manner. These results clearly show the role of the breast stromal fibroblast Atr protein in suppressing tumoregenesis in the breast. Moreover, we have shown that curcumin can normalize the expression/secretion of these factors and therefore reduces the invasion/migration of breast cancer cells in vitro. This indicates that curcumin has potential use as stromal fibroblastnormalizing factor that can be utilized for the inhibition of both cancer initiation and recurrence. Hawsawi, N. M., Ghebeh, H., Hendrayani, S. F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S., and Aboussekhra, A. (2008). Cancer Res 68, 2717-2725. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-02.