Non-Mutated Mediator Genes in Diverse Epithelial Cancer Types

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2017.Cooperation response genes (CRGs) were first identified downstream of cooperating p53 and Ras mutations in colon cancer as non-mutated effector genes that control the cancer phenotype. We postulated that CRGs might play a role in other p53/Ras-driven cancers. To test this, we focused first on basal-like breast cancer (BLBC.) BLBC is an aggressive breast cancer subtype, and the majority of BLBCs are triple-negative, making BLBC insensitive to targeted therapies. This lack of drug responsiveness leaves only conventional chemotherapeutics as a treatment option and results in a consistently poor prognosis. CRGs could represent an important new target in BLBC. Analysis of human triple negative breast cancer (TNBC) samples reveals a subset of CRGs that exhibit concordant dysregulation in BLBC. Perturbations in these genes introduced into human breast cancer cell lines disrupt multiple features of the malignant state while perturbations of these same genes in a normal, non-transformed cell line result in no discernable changes in growth, differentiation or survival. Furthermore, drugs that antagonize the CRG signature result in decreased growth and metabolic activity of cancer cells in vitro, and in vivo treatment with candidate drugs of tumors formed by human breast cancer cells results in a significant decrease in tumor growth. Encouraged by these results, we sought to assess whether CRGs might represent a new target space in a wider set of human epithelial cancers. Mutation analysis of data from human colorectal cancer tissue samples revealed a surprising result: CRG dysregulation arises regardless of the presence or absence of p53 or RAS mutations. Principal components analysis (PCA) of colon, breast, and prostate cancer CRG expression segregates tumor from normal samples but fails to differentiate cancers by underlying mutation or mutation pathway. Interestingly, PCA on CRG expression in bladder cancer fails to differentiate tumor from normal samples, suggesting that CRG expression changes play no role in the pathogenesis of bladder cancer. Finally, increased CRG dysregulation results in significantly decreased survival among breast cancer patients. Taken together, these results suggest that CRG dysregulation might represent a common downstream pathway of a diverse set of initiating oncogenic lesions in multiple cancer types