Background: Obesity in women has been associated with a variety of factors, including genetic predisposition, social class, early age at menarche, exercise, alcohol consumption and diet. Obesity is a risk factor for the occurrence and the recurrence of breast cancer in postmenopausal women, perhaps because of increased exposure to estrogen, insulin and insulin-like growth factors (IGFs). The progesterone receptor (PR) and the steroid hormone receptor coactivator pCIP/ACTR/AIB1/TRAM1/RAC3 (AIB1) are hypothesized to mediate signaling crosstalk between these hormonal pathways. Polymorphisms in both genes have been described and their association with breast cancer risk reported. If genetic factors contribute to obesity, and the PR and AIB1 genes influence estrogenic, insulin and IGF pathways, then genetic patterns resulting from PR and AIB1 polymorphisms may be associated with obesity in postmenopausal women.
Objective: We compared the PR and AIB1 genotypes of postmenopausal women with breast cancer with demographic, disease-related, reproductive, lifestyle and dietary variables in terms of the strength of their relationship with obesity (BMI> or =30 kg/m2).
Subjects: A total of 301 postmenopausal women previously diagnosed with Stage I, II or IIIA breast cancer, who are enrolled in the Women's Healthy Eating and Living (WHEL) study (age: 34.5-70.8 y, BMI: 17.8-54.6 kg/m2).
Measurements: The PR polymorphism PROGINS was identified by PCR. The length of the AIB1 polyglutamine repeat was determined by PCR and nondenaturing gel electrophoresis or DNA sequencing. BMI was obtained at the baseline clinic visit upon entry into the WHEL study. Information about date of diagnosis, stage of disease, tumor hormone receptor status and adjuvant treatment received were obtained from medical records. Reproductive, menstrual history, demographic, family history of cancer, smoking history and exercise frequency and intensity information were obtained from questionnaires. Dietary and alcohol intake data came from four 24-h telephone recalls of food intake obtained at the study entry.
Results: The combined inheritance of PROGINS A1/A1 and AIB1 28/29, 28/30, 28/31, 29/29 or 29/30 (AIB1 LG) genotypes (adjusted odds ratio (OR)=2.22 (95% confidence interval 1.25-3.93)) and early age at menarche (<12 y) (adjusted OR=2.34 (1.12-4.86)) were each associated with the risk for obesity. Current use of tamoxifen (adjusted OR=0.49 (0.28-0.87)) and an alcohol intake > or =10 g/day (adjusted OR=0.28 (0.11-0.77)) were inversely associated with BMI > or =30 kg/m2.
Conclusion: Early age at menarche and a PROGINS A1/A1+AIB1 LG genetic pattern had comparable levels of association with obesity in this cross-sectional sample of postmenopausal women with breast cancer. Since this was a cross-sectional rather than a case-control design, the association between PROGINS and AIB1 genotype and obesity found in this sample should be considered preliminary, and must be re-evaluated with a new and larger sample.