Chaperonin-Containing T Complex (Cct) Is A Novel Target For Treatment Of Metastatic Breast Cancer

e13530 Background: Metastatic breast cancer is uniformly fatal with median survival of 1-2 years. Progressive and refractory disease is the cause. Our group developed a novel cytotoxic peptide, CT20p, and a nanotechnology-based platform to deliver and concentrate CT20p in breast tumors. Using murine xenografts, we found that treatment with nanomolar amounts of CT20p resulted in significant regression of breast cancer tumors. Tumors cells treated with CT20p lost the capacity to rearrange their cytoskeleton and maintain substrate attachment, causing cell death. Methods: To identify the intracellular target of CT20p, we used biotinylated-CT20p to “pull-down” interacting proteins from the cellular lysates of breast cancer cells and normal epithelial cells. Interacting proteins, specific to breast cancer cells, were identified by mass spectrometry. Tissue microarrays (TMAs) for breast cancer were examined by immunohistochemistry for the expression of the interacting proteins. Results were scored and correlated to breast cancer stage, grade and hormone receptor status. Results: We discovered that the intracellular target of CT20p is a protein called chaperonin-containing T-complex (CCT). CCT is a large macromolecular complex composed of 8 subunits that is essential for the folding of actin and tubulin into their native forms. Inhibition of CCT causes the accumulation of unfolded proteins, producing a cell death response such as was observed upon CT20p treatment. CCT expression in cells correlated to susceptibility to killing by CT20p. Using breast cancer TMAs, we observed increased CCT expression in tumor tissues that were stage 2 or higher as compared to cancer adjacent tissues. Increased CCT expression did not correlate with estrogen receptor (ER) levels but did correlate with increased progesterone receptor (PR) levels and Her2/Neu. Tissues from triple negative breast cancer (TNBC) showed a range of CCT expression. Conclusions: These studies suggest that CCT could be novel indicator of breast cancer progression that may be independent of known biomarkers and could be a promising new target for therapeutic intervention, especially in advanced stage breast cancers.