Genetics, Obesity, and Breast Cancer Risk

Institution: University of California, Los Angeles
Investigator(s): Catherine  Carpenter , M.P.H., Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9PB-0117 Award: $517,422
Award Type: Request for Applications
Research Priorities
Etiology>Hormones and nutrition: understanding the modern woman's lifestyle



Initial Award Abstract (2003)
Women who are obese may be more or less likely to develop breast cancer depending upon when during adulthood their obesity occurs. Obese women during the menstrual years have lower chances of acquiring breast cancer, while women who are obese after menopause have greater chances. Obesity occurs for complex reasons. Some of these reasons include: lack of exercise; inheritance of the tendency to be overweight from our parents; hormones; overeating; and environmental factors such as increased reliance on technology and the abundant availability of high-fat inexpensive foods. Two of our previously conducted studies have provided evidence for conducting the proposed research. One study shows that obesity in combination with family history of breast cancer may increase chances of developing breast cancer even further. The second study has determined that a type of a gene for obesity, the leptin-receptor gene (OB-R), was related to amount of body fat among women after menopause.

We propose to study different forms of genes in relationship to breast cancer because genes that increase the likelihood of obesity, may also increase women’s chances of developing breast cancer. Our study will address the following questions:
  1. Are various forms of these candidate genes (leptin-receptor gene (OB-R), beta3 adrenergic gene (beta3-AR), and peroxisome-proliferator-activated receptor gamma 2 gene (PPAR-gamma2) related to obesity among healthy women?
  2. Are various forms of these genes related to chances of developing breast cancer?
  3. Does the relationship between the candidate genes and breast cancer differ according to whether women are lean or obese or whether women are active or inactive?
We will utilize a study of women with breast cancer compared to women without breast cancer that was recently completed in the San Francisco Bay Area. These groups are comprised of women of African American, Caucasian and Hispanic/Latina heritage. The proposed research will use already collected questionnaire data and DNA samples to answer the proposed study questions. Information from a total of 1,500 subjects between the ages of 35 to 79 years (687 women with breast cancer, 813 healthy women) will be available to study. All women of African American, Caucasian or Hispanic/Latina origin that developed breast cancer during 1997 to 1999 in the San Francisco Bay Area were eligible to participate in the study. Healthy women who served as a comparison group were chosen by statistical procedures that generate random telephone numbers. These procedures will enable us to apply our findings to women in general.

The leptin receptor gene has never been studied in relationship to breast cancer. Very recent studies of mice and human tumor tissue have pointed to the possible importance of the leptin receptor and development of breast cancer. Only a very few breast cancer studies have evaluated beta3 AR and PPAR-gamma. We believe results from this study could represent a major breakthrough in understanding the causes of obesity and breast cancer.


Final Report (2007)
Obesity increases the chances of developing breast cancer after menopause. However, prior to menopause, obesity is protective. Genes that promote excess body fat may also be related to breast cancer. We studied three candidate genes for obesity: LEP-R, ADRB3, and PPARgamma2, in a population based case-control study conducted by Dr. Esther John in the San Francisco Bay Area.

Specific Aims:
  1. To evaluate whether the candidate gene variants are associated with obesity among healthy women.

  2. To determine whether the candidate gene variants increase the chances of developing breast cancer.

  3. To determine whether the relationships between candidate gene variants and breast cancer are different according to whether women are lean or obese, or, whether women are active or inactive.

We continued to make progress during the final grant year. Our collaborator, Dr. Sue Ingles, finished genotyping the final candidate gene, ADRB3. Dr. Esther John, from the Northern California Cancer Center, merged the genotype results with the study questionnaire data, and, in addition, conducted validation analyses of the genotype measurements.

In summary, we observed associations for several anthropometric measures (measured waist and hip circumferences) and the LEP-R, (K109R) variant among pre- and postmenopausal healthy obese African American women (controls), and for hip circumference and waist-to-hip ratio in Caucasian healthy obese women (controls). We did not observe associations in Hispanic women, and, we did not observe associations with the two other LEP-R variants, Q223R and K656N. We observed associations between measured waist circumference and waist-to-hip ratio and the PPAR-gamma2 variant, Pro12Ala, among African American healthy women We are about to submit a manuscript summarizing results for LEP-R. We are continuing to conduct analyses on the PPAR-gamma gene and will begin analyses on the ADRB3 gene.

These results are very important to women's health, particularly in terms of our observation that body composition patterns and genetic associations vary according to race/ethnicity, and, in terms of identifying women who may be more susceptible to becoming obese, and, potentially at higher risk for breast cancer. We plan to conduct a diet and exercise intervention among obese postmenopausal women to preliminarily evaluate whether sub-groups of women may be more or less responsive to a weight-loss intervention.


Symposium Abstract (2007)
Introduction: Obesity increases the risk of developing breast cancer after menopause, but before menopause, obesity is protective. Genes the increase the likelihood of obesity may also be related to breast cancer. Objective: We studied the leptin-receptor gene (LEP-R) in relationship to body composition because the leptin-receptor may share functional pathways with breast cancer.

Methods: We conducted a candidate gene study of LEP-R among two study populations: a clinical sample of 36 healthy, overweight to obese postmenopausal women of Caucasian and African-American ancestry (age 45 to 72 y); and, a population-based sample of 729 pre- and postmenopausal healthy women (age 35 to 79 y) who were Caucasian, African-American and Hispanic. Both studies measured waist and hip circumferences, height and weight. The clinical study assessed total body fat using DEXA (dual-energy X-ray absorptiometry). For the clinical study, we genotyped LEP-R variants, K109R, Q223R with restriction endonuclease digestion; and K656N using direct sequencing. We genotyped the population sample using Taqman. We adjusted statistical association models for age (clinical sample), or, for age and menopausal status (population-based sample).

Results: In the clinical sample, we observed an association between percent body fat and the K109R variant (age-adjusted p=0.01), that appeared to be limited to African-American women. In the population sample, we observed associations of K109R with waist-to-hip ratio (WHR) among Caucasians (p = 0.03) and with waist circumference among African-Americans (p = 0.03). We stratified the population sample by body-mass index (BMI) greater than or equal to 30.0, the clinical cut-point for obesity. Among Caucasian obese women (BMI > 30.0), both WHR (p=0.006) and hip circumference (p=0.05) were associated with K109R, while waist (p = 0.009) and hip (p=0.06) were associated among African American obese women. The other LEP-R variants Q223R and K656N were not associated in either study sample. No associations were observed for Hispanic women.

Conclusion: The findings suggest that the LEP-R variant, K109R, may be associated with body fat and body fat distribution among overweight to obese women.