title: The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer.
abstract: CYP3A4 is involved in the metabolism of endogenous steroids, and an allelic variant, CYP3A4*1B, consisting of an A to G polymorphism within the 5'-flanking region termed the nifedipine-specific response element (NFSE) has been associated with high grade and advanced stage of prostate cancers. Because steroid hormone exposure is known to influence breast and ovarian cancer risk, we conducted case-control studies to assess the relationship between CYP3A4*1B and risk of breast or ovarian cancer. CYP3A4 NFSE genotype was determined in 951 breast cancer cases and 500 controls frequency matched for age and 488 ovarian cancer cases and 276 controls of similar age distribution. Case-control analyses and comparisons of genotype distributions were conducted by unconditional logistic regression. In addition, the functional significance of the CYP3A4*1B polymorphism was assessed by analysis of CYP3A4-reporter gene constructs transiently transfected into liver-derived cell lines and primary cultures of well-differentiated rat hepatocytes. The GG genotype was rare in all groups (0-0.4%). There was no risk of cancer associated with the AG/GG genotypes combined, with an OR (95% CI) of 0.86 (0.54-1.33) for breast cancer (P = 0.5), and 1.51 (0.80-2.89) for ovarian cancer (P = 0.2). Analysis of CYP3A4-luciferase constructs showed that CYP3A4*1B did not consistently affect reporter gene activity. Our data suggest that the CYP3A4*1B polymorphism is not associated with risk of breast or ovarian cancer. In support of this negative finding, in-vitro functional studies indicate that NFSE genotype is not a critical factor in the transcriptional activity of the CYP3A4 5'-flanking region, and is thus unlikely to modulate CYP3A4-mediated metabolism of steroids.
authors.affiliation: Cancer and Cell Biology Division, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research and The University of Queensland, Brisbane, Australia. mandyS@qimr.edu.au
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Bryan
authors.initials: B
authors.lastname: Goodwin
authors.forename: Ecushla
authors.initials: E
authors.lastname: Hodgson
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: David M
authors.initials: DM
authors.lastname: Purdie
authors.forename: Margaret R E
authors.initials: MR
authors.lastname: McCredie
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D001315:Australia / Q000453:epidemiology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D007407:Interviews as Topic; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D015183:Restriction Mapping; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D020121:5' Untranslated Regions; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human