Correlates of obesity in postmenopausal women with breast cancer: comparison of genetic, demographic, disease-related, life history and dietary factors

Abstract

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 (BMIZ30 kg/m 2 ). 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/m 2 ). 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) ¼ 2.22 (95% confidence interval 1.25-3.93)) and early age at menarche (o12 y) (adjusted OR ¼ 2.34 (1.12-4.86)) were each associated with the risk for obesity. Current use of tamoxifen ) and an alcohol intake Z10 g/day (adjusted OR ¼ 0.28 (0.11-0.77)) were inversely associated with BMI Z30 kg/m 2 . CONCLUSION: Early age at menarche and a PROGINS A1/A1 þ 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.

Genetic and environmental correlations between obesity phenotypes and age at menarche

“…In contrast to the results of Wasserman et al, 6 in 140 unrelated postmenopausal subjects, we did not find significant correlations between obesity phenotypes and AAM. The results, however, are consistent with the findings of Kirchengast et al, 47 where postmenopausal women exhibited less significant correlation between fat mass and AAM than premenopausal women.…”

“…A number of studies have suggested association between AAM and obesity phenotypes. [1][2][3][4][5][6] In a longitudinal study of the northern Finland birth cohort, the proportions of overweight and obese females were significantly higher in those who had earlier menarche. 3 Consistent with that, Wasserman et al 6 found that early menarcheal ages (o12 years) were associated with the risk for obesity in postmenopausal women.…”

Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus and Accumulation of Malonyl-CoA

“…Despite its widespread use, the action of TMX on human body weight is controversial. Data from the WHEL (Women's Healthy Eating and Living) clinical trial show that obese women with breast cancer under TMX treatment had a decreased BMI (48). However, measurement of BMI in this study occurred at varying times after breast cancer diagnosis and thus did not necessarily reflect prediagnosis BMI.…”

Impact of Body Mass Index on Prognostically Relevant Breast Cancer Tumor Characteristics

“…Accordingly, Wasserman et al [46] observed no association between BMI and disease stage at diagnosis in 301 postmenopausal women of the Women's Healthy Eating and Living study. The same was true for women of any age in another study [47].…”