NKX3.1 Genotype and IGF-1 Interact in Prostate Cancer Risk
Annual rept. 1 May 2008-30 Apr 2009
COLUMBIA UNIV NEW YORK
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NKX3.1 is a prostate-specific homeobox gene that maps to chromosome 8p21, the most frequent target for loss of heterozygosity in prostate cancer. NKX3.1 is a haploinsufficient tumor suppressor in the prostate. We found that IGFBP-3expreession was activated 10-fold by NKX3.1 in cell lines and tissues. IGFBP-3 is an inhibitor of IGF-1, a serum component that when elevated is a risk factor for prostate cancer. NKX3.1 expression inhibits IGFIR signaling and diminishes IRS-1 phosphorylation. Knock down of IGFBP-3 attenuates the growth suppressive effects of NKX3.1. NKX3.1 C154T is a polymorphic allele present in 10 of the population. The polymorphic allele codes for a variant protein that replaces arginine 52 with cysteine. NXK3.1 C154T confers a minimally increased risk for prostatic enlargement and for prostate cancer. In a cohort of cases and controls with known NKX3.1 genotype we found that the effect of serum IGF-1 on prostate cancer risk was seen only in men with at least one polymorphic NKX3.1 allele. Consistent with its apparent interaction with IGF-1 in prostate cancer risk, NKX3.1 R52C protein is attenuated in activation of IGFBP-3. The data therefore show that the two prostate cancer risk factors, NKX3.1 R52C and circulating IGF-1 interact. NKX3.1 R52C activates less IGFBP-3 expression than its wild type counterpart and thereby predisposes prostate epithelial cells to the proliferative and antiapoptotic effects of IGF-1, increasing the risk for prostate cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research