Colorectal cancer remains to be the second most lethal cancer in the US. More than 50,000 people die of it each year. With clear demand, much effort is being made to develop therapeutic and chemopreventive drugs for colon cancer. However, all drugs developed so far have had large non-responsive patient populations for two reasons;(1) """"""""Colon cancer"""""""" is a collection of cancers whose cause and aggravating factors differ. A variety of factors including age, environments, smoking habit, diet and certain genetic predispositions play a role in the development, resulting cancers with different molecular causes. A drug targeting a specific cause often fails against cancers with other causes, and (2) Translational research and drug development system depends on animal models, and current line up of animal models does not comprehensively address different cancer causes. Colon cancers with certain type of molecular causes manage to escape from getting targeted in the process of drug discovery and translational efforts. A prevailing biological trait of human colon cancer is high degree of chromosome instability (CIN). 85% of human colon cancers show CIN. It is hypothesized that high CIN accelerates loss of tumor suppressors and/or gain of oncogenes. A major cause for CIN is a defect in chromosome cohesion, a molecular mechanism involved in tethering chromosomes together. Genes involved in chromosome cohesion are frequently mutated in colon cancer. However, animal models involved in chromosome cohesion and CIN have never been used for colon cancer study or for drug development, under- representing the significant biological process in current drug development system. In this study, we will validate Sgo1 haploinsufficient transgenic mice as a new model for colon cancers aggravated by chromosome cohesion defect and high CIN. We will (i) determine role of Sgo1 in colon cancer development, (ii) identify consequences of Sgo1 mutation with histological and protein marker expression analyses, and (iii) test the hypothesis by analyzing chromosome loss or gain specific to Sgo1 mice compared with wild type control with Comparative Genomic Hybridization (CGH) technique in normal-looking colonic mucosal tissue and in colon tumors. Once validated, the model will aid identifying drugs that work for human population so far non- responsive to existing drugs.

Public Health Relevance

We will test and validate novel transgenic mouse model for colon cancer study. The new model represents a common type of mutation in human colon cancer. The model will aid identifying novel class of drugs, chemopreventive and therapeutic, that work for human population so far non-responsive to existing drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-SRLB-2 (J1))
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Perloff, Marjorie
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University of Oklahoma Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
Oklahoma City
United States
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Rao, Chinthalapally V; Asch, Adam S; Yamada, Hiroshi Y (2017) Emerging links among Chromosome Instability (CIN), cancer, and aging. Mol Carcinog 56:791-803
Yamada, H Y; Kumar, G; Zhang, Y et al. (2016) Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung. Oncogenesis 5:e256
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Yamada, Hiroshi Y; Zhang, Yuting; Reddy, Arun et al. (2015) Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice. Carcinogenesis 36:429-40
Rao, Chinthalapally V; Kurkjian, Carla D; Yamada, Hiroshi Y (2012) Mitosis-targeting natural products for cancer prevention and therapy. Curr Drug Targets 13:1820-30