Regulation of prostatic cell growth is controlled, at least in part by steroid hormones and particularly androgens or male hormones. Epidemiological investigations have revealed that testosterone levels are relatively high in African-Americans and lower in Asians and Caucasians, a pattern that is reminiscent of the risk for developing prostate cancer among racial/ethnic groups. The normal (and abnormal) genetic variations in steroid hormone-metabolic genes in human populations are only poorly characterized and not well understood at this time. It is our hypothesis that genetic variants of human androgen- metabolic enzymes contribute significantly to androgen levels and risk for prostate cancer. We propose to identify and characterize in genetic and biochemical detail common cSNPs (coding region single nucleotide polymorphisms) in a human hormone-metabolic genes with relevance to predisposition to prostate cancer and male reproductive biology in general, the HSD17B3 gene which encodes the testicular or type III 17beta- hydroxysteroid dehydrogenase enzyme. This enzyme converts the precursor adrostenedione into testosterone, the male hormone. We propose to identify cSNPs in four large racial/ethnic population in the US: African-Americans, Asians, Caucasians and Latinos that are also at very different risk for prostate cancer. African- Americans have a very high risk for the disease, while Asians have relatively low risk. CSNPs will be identified by automated DNA sequencing of PCR (polymerase chain reaction)-amplified exonic DNA. Missense mutations will be reconstructed in the cDNA and over- expressed to assess the functional significance of these particular cSNPs. Thus, we intend to investigate the following two specific aims: 1) To identify constitutional (""""""""germline"""""""") DNA mutations (particularly cSNPs) in a male hormone-metabolic gene, HSD17B3, in four racial/ethnic groups; and 2) to establish the in vitro biochemical properties of all missense mutations identified in 1. In summary, we will investigate the molecular genetics of natural variation in an androgen-metabolic gene in four different racial/ethnic populations. Our studies will have relevance to the understanding of predisposition to prostate cancer as well as male reproductive biology and its aberrations. The investigations proposed here will lead to a molecular epidemiologic analysis of prostate cancer risk in various racial/ethnic groups.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA083112-01
Application #
2907324
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M2))
Program Officer
Verma, Mukesh
Project Start
1999-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Makridakis, Nick M; Reichardt, Juergen K V (2004) Molecular epidemiology of androgen-metabolic loci in prostate cancer: predisposition and progression. J Urol 171:S25-8; discussion S28-9
Makridakis, N M; Reichardt, J K (2001) Molecular epidemiology of hormone-metabolic loci in prostate cancer. Epidemiol Rev 23:24-9
Novelli, G; Margiotti, K; Sangiuolo, F et al. (2001) Pharmacogenetics of human androgens and prostatic diseases. Pharmacogenomics 2:65-72