NKX3.1 Genotype and IGF-1 Interact in Prostate Cancer Risk

PUBLIC ABSTRACT

This proposal focuses on a newly defined risk factor for prostate cancer that could be applied very rapidly in the community to identify men at a two- to threefold increased risk for the disease using a simple test for a genetic polymorphism and a serum test for IGF-1. We have found that the NKX3.1 C154T polymorphism present in 11% of the population without regard to race interacts with serum IGF-1 levels to sensitize men to IGF-1-associated carcinogenesis. The genetic variant NXK3.1 C154T confers a minimally increased risk for prostatic enlargement and for prostate cancer. High serum levels of IGF-1 are a known risk factor for prostate cancer. In a cohort of 936 cases and controls, we found that the effect of serum IGF-1 on prostate cancer risk was not seen in men homozygous for wild-type NKX3.1, but prostate cancer risk caused by elevated circulated IGF-1 was increased almost threefold in men with at least one polymorphic NKX3.1 allele (OR=2.75, 95%CI 1.12-6.76). NKX3.1 activates expression of IGFBP-3, an IGF-1 binding protein, approximately 10-fold in both cell lines and tissues. The variant NKX3.1 R52C protein is attenuated compared to wild-type NKX3.1 in activation of IGFBP-3 expression. We hypothesize that NKX3.1 R52C activates less IGFBP-3 than its wild-type counterpart and thereby predisposes prostate cells to the growth-promoting and survival effects of IGF-1. This work has the potential of validating a screening test for men at high risk for aggressive prostate cancer. Validation of this test could bring it to the market place in less than 2 years as all the technology is currently being applied widely for molecular diagnostics.