title: The joint effect of smoking and AIB1 on breast cancer risk in BRCA1 mutation carriers.
abstract: Women with BRCA1 mutations are at an elevated risk for breast cancer. AIB1 (NCOA3/SRC3) genotype and smoking may alter this risk. We examined the differences in breast cancer risk by AIB1 polyglutamine repeat polymorphism and pre-diagnosis smoking habits for BRCA1 mutation carriers to determine if there was an interaction between smoking and AIB1 genotype. Multivariate Cox proportional hazards regression was used with 316 female BRCA1 mutation carriers to model breast cancer risk. Ever having smoked was associated with a decreased breast cancer risk [Hazard Ratio (HR) = 0.63, 95% CI, 0.47-0.87]. A dose-response relationship between number of pack-years smoked and breast cancer risk was also found for women who smoked <20 pack years of cigarettes (HR = 0.72, 95% CI, 0.52-1.00) and for women who smoked >/=20 pack years (HR = 0.41, 95% CI, 0.23-0.71; P for trend = 0.0007). Women with a 28 repeat allele for AIB1 had a significantly reduced risk of breast cancer (HR = 0.72, 95% CI, 0.51-1.00). Women who smoked >/=20 pack-years with a 28 repeat allele had an even greater reduced risk of breast cancer (HR = 0.19, 95% CI, 0.07-0.54) compared to women who were never smokers with no 28 allele. Since AIB1 appears to modulate the effect of endogenous hormones via the estrogen receptor, and smoking affects circulating hormone levels, these results support evidence that steroid hormones play an important role in breast carcinogenesis in BRCA1 mutation carriers, and suggest mechanisms for developing novel cancer prevention strategies for BRCA1 mutation carriers.
authors.affiliation: Department of Biostatistics and Epidemiology and Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. scolilla@cceb.med.upenn.edu
authors.forename: Susan
authors.initials: S
authors.lastname: Colilla
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000502:physiology*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D051548:Histone Acetyltransferases; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*
chemical_list: D015513:Oncogene Proteins; D015534:Trans-Activators; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3