Interrelationships of Diet, Physical Activity, and Hormones with Breast Cancer Risk

Joanne F. Dorgan, M.P.H., Ph.D., Member Ryan Hopson, Research Study Assistant Kathleen Lugas, Secretary

Breast cancer is a hormonally dependent cancer. In a pooled analysis of world-wide data (Breast Cancer Collaborative Group, J. Natl. Cancer Inst. 94:606, 2002), we found that postmenopausal women with elevated serum estrogen and androgen levels are at a signicantly increased risk of developing breast cancer. We continue to conduct research aimed at identifying biomarkers associated with breast cancer risk. These studies not only increase our understanding of breast cancer etiology, but also could identify women at increased risk of breast cancer. Furthermore, biomarkers associated with risk can be used as endpoints in trials to evaluate effectiveness of interventions to prevent cancer. Numerous health behaviors including diet, alcohol ingestion, and physical activity could inuence breast cancer risk through effects on serum hormones and breast density. Because most breast development occurs during adolescence, our studies focus not only on adult exposures but also on adolescent exposures. The etiology of most chronic disease is complex and is believed to involve the interaction of genetics and the environment. Rapid advances in genetics over the past decade coupled with development of high throughput technologies provide an unprecedented opportunity to determine the contributions of genetics and the environment to health and disease. Large-scale epidemiologic studies of gene-environmental interactions are now needed to take advantage of this tremendous opportunity to identify the causes of disease and treatment outcomes so that interventions can be developed to improve health. Our pilot study suggests that a prospective cohort study to identify gene-environment interactions related to cancer etiology and outcomes is feasible and could provide results within 10 years.
Serum biomarkers and cancer risk. Dorgan, in collaboration with Spittle, Weaver, Brinton,a Chandlerb

We have conducted several prospective studies of serum biomarkers and breast cancer risk based on the Columbia, MO Serum Bank. Some of our salient results include positive associations of serum estrogen and androgen levels with subsequent breast cancer in postmenopausal women (Dorgan et al., Cancer Epidemiol. Biomark. Prev. 5:533, 1996; Dorgan et al., Cancer Epidemiol. Biomark. Prev. 6:177, 1997); inverse associations of serum carotenoids with breast cancer risk (Dorgan et al., Cancer Causes Control 9:89, 1998); and no association of pesticides and PCBs with breast cancer risk (Dorgan et al., Cancer Causes Control 10:1, 1999). More recently, we completed a longterm follow-up of Columbia, MO Serum Bank participants. The follow-up was highly suc-

cessful. Of the 6,720 women included in the extended follow-up, 6,154 (91.6%) were located; 566 (8%) were not locatable, 109 (2%) refused to participate, and 40 (<1%) were too ill to participate. 1,694 women (25%) are deceased. A total of 400 women included in the cohort have been identied as having been diagnosed with breast cancer. In preparation for future analytical studies, we are conducting a pilot study to evaluate assay reliability and within person variation of several adrenal hormones. Coefcients of variation (CVs) were 7.7% for cortisol, 20% for 11desoxycortisol, 18.3% for pregnenolone, 35.3% for 17OH-pregnenolone, and 14.5% for progesterone. Intraclass correlation coefcients (ICCs), which are close to one if differences in measurements between subjects are large compared to total assay variability, were .96 for cortisol, .76 for 11-desoxycortisol, .85 for pregnenolone, .85
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Fox Chase Cancer Center 2005 Scientic Report

for 17OH-pregnenolone, and .95 for 17OHprogesterone. We currently are evaluating variation in serum levels of these adrenal hormones over time in the same women. We also are conducting a pilot study to evaluate assay reliability and within person variation in Mllerian inhibiting substance (MIS). This hormone is secreted by the ovaries and has been implicated in breast and ovarian cancer risk. The CV of the MIS assay was 14.6% and the ICC was .99 indicating that assay variation is small relative to between person variation in MIS levels. We currently are evaluating variation in serum levels of MIS over time in the same women.
Childhood diet, serum hormones and breast cancer susceptibility. Dorgan, in collaboration with Barton,c Kwiterovich,d Lasser,e Stevens,f Robson,g Van Horn,h Snetselaar,i Shepherd,j Hilton,j Himesk

luteal phase progesterone levels compared to girls in the usual care group (Dorgan et al., J. Natl. Cancer Inst. 95:132, 2003). These ndings suggest that the DISC intervention altered function of the hypothalamic-pituitary-ovarian (HPO) axis. Although it is currently unknown whether these changes will ultimately inuence participants risk of developing breast cancer as adults, estradiol and progesterone are both breast mitogens that regulate breast development during puberty. We currently are conducting a long-term follow-up of DISC girls, who are now in their twenties, to evaluate the effect of the DISC intervention during puberty on biomarkers associated with breast cancer risk, including serum hormones, bone mineral density, and breast density. This unique opportunity will greatly improve our understanding of the effects of adolescent diet on breast development and possibly the origins of breast cancer.
Alcohol and breast cancer in postmenopausal women. Dorgan, in collaboration with Baer,o Albert,a Corle,a Judd,o Hartman,p Chandler,b Stanczyk,q Taylora

Animal and ecologic studies strongly support a role of diet in the etiology of breast cancer, but results of case-control and cohort studies are equivocal. Adolescence is a time of rapid growth and maturation of the breasts, and a womans diet as an adolescent may affect her risk of developing breast cancer more than her diet as an adult. Because of difculties remembering exposures in the distant past, there is considerable potential for misclassication bias in case-control studies of adult breast cancer that attempt to evaluate recalled adolescent diet. Cohort studies begun today to evaluate the effect of childhood and adolescent diet on breast cancer risk will not begin to yield results for 4050 years. Alternative strategies are clearly needed. The Dietary Intervention Study in Children (DISC) was a multicenter, randomized controlled clinical trial that evaluated the effect of a reduced fat dietary intervention during puberty on serum sex hormones in 301 girls who were healthy 810 year olds at randomization. After 5 years of participation, girls in the intervention group had signicantly 30% lower estradiol and non-SHBG bound estradiol, 21% lower estrone, and 29% lower estrone sulfate levels during the follicular phase of their menstrual cycles compared to girls in the usual care group. After 7 years, differences in estrogens were no longer apparent, but girls in the intervention group had signicantly 53% lower

Alcohol ingestion is positively related to breast cancer risk in most epidemiologic studies, but results are inconsistent at lower levels of intake, and a biological mechanism for the association has not been established. We performed a controlled feeding study to evaluate the effect of chronic moderate alcohol ingestion on serum levels of hormones and other biomarkers. Participants included 51 healthy postmenopausal women not using hormone replacement therapy. Each participant consumed 15 gm alcohol/ day, 30 gm alcohol/day, or a placebo beverage during one of three 8-week dietary periods. All food and beverages were supplied by the study during the dietary periods, and energy intake was adjusted to keep body weight constant. Hormones and other biomarkers were measured in serum collected at the end of each dietary period. When consuming 15 gm and 30 gm alcohol/day, respectively, participants estrone sulfate concentrations increased by 7.5% and 10.7%, and their DHEAS concentrations increased by 5.1% and 7.5% (Dorgan et al., J. Natl. Cancer Inst. 93:710, 2001). None of the other hormones measured changed signicantly. Women with elevated levels of estrone sulfate and DHEAS are at an increased
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risk of breast cancer, and these results suggest a mechanism by which consumption of 1 to 2 alcoholic drinks/day by postmenopausal women could increase their breast cancer risk. Heavier postmenopausal women are at an increased risk of breast cancer, and alcohol could also potentially inuence breast cancer risk through effects on energy balance. Leptin is involved in energy balance and has been hypothesized to play a role in carcinogenesis. We found that alcohol ingestion increases serum leptin levels in postmenopausal women (Roth et al., J. Natl. Cancer Inst. 95 :1722, 2003). When consuming 15 gm and 30 gm alcohol/day, respectively, participants leptin levels rose by 7.3% and 8.9% compared to consuming no alcohol. Alcohol ingestion could further increase breast cancer risk by increasing oxidative stress (1). When consuming 30 gm alcohol/day, participants serum -tocopherol decreased by 4.6%, while their isoprostane levels increased by 4.9%. Folate and vitamin B12 are required for DNA methylation and nucleotide synthesis. Effects on these vitamins could potentially mediate the association of alcohol on breast cancer risk. Lower levels of folate and vitamin B12 among heavy drinkers are well established, but effects of moderate drinking are less clear. In our study (Laufer et al., Eur. J. Clin. Nutr. 8:1518, 2004), consumption of 30 gm alcohol/day
Publications

resulted in a signicant 5% decrease in vitamin B12. However, methylmalonic acid, a sensitive functional indicator of vitamin B12 status, was unchanged. Serum folate levels also were not changed signicantly when consuming 15 30 gm alcohol/day, although homocysteine levels increased signicantly by 3% when women consumed 30 gm alcohol/day. Increased concentrations of insulin-like growth factor-I (IGF-I) and decreased concentrations of its principal binding protein (IGFBP3) have been associated with cancer at several sites. Although observational studies suggest a potential effect of alcohol on levels of IGF-1 and IGFBP-3, controlled feeding studies have not been conducted previously. We found that consumption of 15 gm alcohol/day did not affect serum IGF-I concentrations but signicantly increased IGFBP-3 levels, whereas consumption of 30 gm alcohol/day signicantly decreased IGF-I concentrations but did not change IGFBP-3 levels (2). Alcohol ingestion could increase cancer risk via oxidative DNA damage. In our study however, alcohol ingestion did not increase oxidative DNA damage measured by 5-hydroxymethyl-2-deoxyuridine (5-HMdU) autoantibodies in serum (3). Eight weeks may be too short an interval to observe measurable differences in oxidative DNA damage measured by 5-HMdU. Future studies will use a panel of biomarkers of DNA damage.

1. Hartman, T.J., Baer, D.J., Graham, L.B., Stone, W.L., Gunter, E.W., Parker, C.E., Albert, P.S., Dorgan, J.F ., Clevidence, B.A., Campbell, W.S., Tomer, K.B., Judd, J.T., Taylor, P.R. Moderate alcohol consumption and levels of antioxidant vitamins and isoprostanes in postmenopausal women. Eur. J. Clin. Nutr. 59:161-168, 2005. 2. Lavigne, J.A., Baer, D.J., Wimbrow, H.H., Albert, P.S., Brown, E.D., Judd, J.T., Campbell, W.S., Giffen, C.A., Dorgan, J.F Hartman, T.J., Barrett, J.C., Hursting,, S.D., Taylor, P.R. Effects of alcohol on insulin-like growth ., factor-I and insulin-like growth factor binding protein-3 in postmenopausal women. Am. J. Clin. Nutr. 81:503-507, 2005. 3. Mahabir, S., Baer, D.J., Johnson, L.L., Frenkel, K., Dorgan, J.F Campbell, W., Hartman, T.J., Clevidence, B., ., Albanes, D., Judd, J.T., Taylor, P.R. No association between alcohol supplementation and autoantibodies to DNA damage in postmenopausal women in a controlled feeding study. Eur. J. Cancer Prev. 14:427-429, 2005.
a b c d e f g h i j

Fox Chase researcher L.A. Brinton, P. Albert, D. Corle, P.R. Taylor: National Cancer Institute, Bethesda, MD D.W. Chandler: Esoterix Endocrinology, Calabasas Hills, CA B.A. Barton: Maryland Medical Research Institute, Baltimore, MD P.J. Kwiterovich: Johns Hopkins University, Baltimore, MD N.L. Lasser: New Jersey Medical School, Newark, NJ V.J. Stevens: Kaiser Permanente Center for Health Research, Portland, OR A.M. Robson: Childrens Hospital, New Orleans, LA L. Van Horn: Northwestern University Medical School, Chicago, IL L. Snetselaar, R.M. Lauer: University of Iowa, Iowa City, IO J. Shepherd, N. Hilton: University of San Francisco, San Francisco, CA

Fox Chase Cancer Center 2005 Scientic Report

k J. Himes: University of Minnesota, Minneapolis, MN l E. Obarzanek: National Health, Lung and Blood Institute, Bethesda, MD m S.Y.S. Kimm: University of Pittsburgh, Pittsburgh, PA n R.P. McMahon: University of Maryland, Baltimore, MD o D. Baer, J.T. Judd: Agriculture Research Service, U.S.D.A., Beltsville, MD p T.J. Hartman: Pennsylvania State University, University Park, PA q F Stanczyk: University of Southern California School of Medicine, Los .Z.

Angeles, CA

Fox Chase Cancer Center 2005 Scientic Report