CYP3A4 Polymorphisms—Potential Risk Factors for Breast and Prostate Cancer: A HuGE Review

• Published in: American journal of epidemiology Vol. 160; no. 9; pp. 825 - 841
• Main Authors: Keshava, Channa, McCanlies, Erin C., Weston, Ainsley
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01.11.2004; Oxford Publishing Limited (England)
• Subjects: African Americans - genetics; Analysis. Health state; Androgens - metabolism; Australia - epidemiology; Biological and medical sciences; Breast cancer; breast neoplasms; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carcinogens - metabolism; Case-Control Studies; confidence interval; CYP3A4; Cytochrome P-450 CYP3A; cytochrome P-450 enzyme system; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Enzymes; Epidemiologic Studies; Epidemiology; Female; Gene Expression Regulation, Neoplastic; Gene Frequency - genetics; General aspects; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Genetic Variation - genetics; genetics; Genotype; Gynecology. Andrology. Obstetrics; hormones; Humans; Liver; Male; Mammary gland diseases; Medical sciences; metabolism; Molecular Epidemiology; Nephrology. Urinary tract diseases; odds ratio; PCR; polymerase chain reaction; Polymorphism, Genetic - genetics; Prevalence; Prospective Studies; Prostate cancer; prostatic neoplasms; Prostatic Neoplasms - epidemiology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Public health. Hygiene; Public health. Hygiene-occupational medicine; Risk Factors; Scotland - epidemiology; Sequence Analysis, DNA; Steroids; the gene coding for the cytochrome P-450 enzyme designated CYP3A4; Tumors; Tumors of the urinary system; United States - epidemiology; untranslated region; Urinary tract. Prostate gland; UTR; Australia; USA; Africa; Prostate disease; Isozyme; Pathogenesis; hormones; Breast tumor; breast neoplasms; Review; CYP3A4; Genetic determinism; Epidemiology; Genetics; cytochrome P-450 enzyme system; Mammary gland; Male genital diseases; Public health; Human; Hormone; Urinary system disease; Enzyme; Cytochrome P450; Breast cancer; Malignant tumor; Mammary gland diseases; Risk factor; prostatic neoplasms; metabolism; Prostate cancer; Bibliographic review; Polymorphism
• ISSN: 0002-9262; 1476-6256; 0002-9262
• DOI: 10.1093/aje/kwh294

The steroid hydroxylase CYP3A4 is the most abundant P-450 enzyme in the human liver, and CYP3A enzymes metabolize more than 50% of prescription drugs. The CYP3A4 gene is expressed in the liver, gut, colon, prostate, and breast. Individual variation in CYP3A4 may play a role in breast and prostate carcinogenesis through modulation of sex hormone metabolite levels. Alternatively, CYP3A4 can metabolically activate exogenous carcinogens. CYP3A4 activity varies widely in humans, and more than 78 DNA sequence polymorphisms are known. These observations prompted the hypothesis that variant CYP3A4 may be involved in breast and prostate cancer. Two epidemiologic studies of breast cancer and five of prostate cancer examined CYP3A4 genotypes. A US study showed that inheritance of CYP3A4*1B correlates with early menarche, a breast cancer risk factor. However, an Australian breast cancer case-control study found no association with CYP3A4*1B. Two Scottish prospective studies showed CYP3A4*1B to be a risk factor for prostate cancer among men with benign prostatic hyperplasia. Three other studies were undertaken in the United States: two were case-only studies and the other was a case-sibling control study. Although results for African Americans were inconsistent, these studies suggested that CYP3A4*1B was associated with markers of advanced disease. These observations support the notion that development of robust, conventional molecular epidemiologic case-control studies to address these questions, including gene-gene and gene-environment interactions, will be timely.