Regina G. Ziegler, Ph.D., M.P.H.

Senior Investigator



9609 Medical Center Drive
Room SG/6E106
Rockville, MD 20850


Research Topics

Multidisciplinary Studies of Diet, Nutrition, and Cancer

Vegetables, Fruits, and Carotenoids

Previously, we demonstrated that diets high in vegetables, fruits, and carotenoids were strongly associated with reduced risk of lung and upper aerodigestive tract cancers. To explore the individual contributions of the major carotenoids, we conducted nested case control studies in the Honolulu Heart Program cohort. High serum levels of several carotenoids were associated with decreased risk of lung, oral pharyngeal, esophageal, and laryngeal cancer, with a-carotene the most predictive. Recently, in the Nurses and Health Professionals cohorts, using repeated dietary measures, we found that high vegetable and fruit intake was associated with only a modestly reduced risk of lung cancer in women and no risk reduction in men. Our analyses suggested that the strength of this widely accepted relationship might have been exaggerated because confounding by smoking has not always been adequately controlled. Since other recent publications have questioned whether vegetable intake can reduce the risk of colorectal cancer, we are exploring opportunities to continue to evaluate the importance of vegetables and fruits in cancer etiology, with emphasis on prospective studies, range and variety in intake, and accurate assessment of exposure. Initially, we will explore vegetable and fruit intake, circulating levels of individual carotenoids, and risk of colorectal polyps at various stages in the speculated progression to cancer, using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.

Lycopene, a carotenoid concentrated in tomato products, has been linked to reduced risk of prostate cancer in several studies. In a case control study conducted among U.S. blacks and whites, we found that high circulating lycopene was protective in both races. In addition, circulating levels were lower in the blacks, which suggested that low lycopene might contribute to the substantially higher rates of prostate cancer among U.S. blacks. The protective influence of lycopene rich diets has been most consistently seen in U.S. studies, so we are now exploring the influence of high circulating lycopene in a cohort of Finnish men with distinct dietary patterns.

One-Carbon Metabolism

Disruption of one carbon metabolism can interfere with DNA synthesis, repair, and methylation and thus promote carcinogenesis. Efficient one carbon metabolism requires not only folate but also vitamins B2, B6, and B12 and optimal activity of multiple enzymes, such as methylene tetrahydrofolate reductase and methionine synthase. In a community based case control study of invasive cervical cancer in five areas in the U.S., we found that low serum and red blood cell folate were only modestly predictive of increased risk. However, elevated serum homocysteine was strongly and significantly predictive (RR's~2 3), which suggested that pervasive problems in one carbon metabolism might be involved. We are now assessing the contribution of B vitamin inadequacies and common polymorphisms in key one carbon metabolism genes. In addition, we will be evaluating the importance of one carbon metabolism in the etiology of brain and colorectal cancer. Dietary and vitamin supplement information are being analyzed in a multicenter case control study of brain cancer, and will be complemented by assays for genetic polymorphisms. In the PLCO cohort, 2,400 men and women were diagnosed with colorectal adenomatous polyps at baseline. The dietary information, serum, and DNA collected in this study will allow us to relate the role of one carbon metabolism to the speculated progression of colorectal cancer. Since folic acid fortification has already been shown to decrease homocysteine levels in populations with a variety of nutritional and genetic impairments, our results may indicate how targeted supplementation and/or fortification schemes may contribute to cancer prevention.

Breast Cancer

International variation in breast cancer incidence and migrant studies indicate that modifiable factors play a major role in breast cancer etiology, although the specific lifestyles and environmental exposures remain elusive. We designed a large, population-based case-control study of breast cancer in Asian-American women to take advantage of their diversity in diet and breast cancer risk. Childhood, adolescent, and adult exposures were assessed by interviewing both study participants and their mothers. To complement the extensive interview information, body size and shape were measured, and blood and urine samples were collected. Endogenous hormones, phytoestrogens, growth factors, micronutrients, and fatty acids have been or will be measured in selected specimens. We found a 6-fold gradient in breast cancer risk by migration history within our study population, comparable to the international differences in breast cancer incidence rates. Exposures during adult life substantially influenced risk. Furthermore, there was no evidence of an especially susceptible period during menarche or early reproductive life. Increased adiposity and weight gain in the decade preceding diagnosis were critical determinants of risk. Thus, excess weight may function as a late stage promoter in breast carcinogenesis, and weight maintenance or reduction as an adult may have a significant and rapid impact on breast cancer risk. We are currently exploring which endogenous hormones, hormone metabolites, growth factors, and dietary patterns are most correlated with migration history, and thus likely determinants of the 6-fold gradient in breast cancer incidence. Circulating estrogens were only weakly associated with Westernization, while circulating androgens were inversely associated in both pre- and postmenopausal women. Decreased intake of soy was associated with a doubling of breast cancer risk. We now want to examine the broader dietary patterns associated with soy intake; in particular, its relationship to vegetable, fruit, and grain consumption; the relative contributions of childhood and adult soy intake; and what specific isoflavones and lignans seem important. Since height was a strong and consistent predictor of risk in these Asian-American women, we are seeking biologic explanations, with emphasis initially on insulin-like growth factors.


Dr. Ziegler is currently a senior investigator in the Office of the Director of the Epidemiology and Biostatistics Program of the National Cancer Institute. Her research on diet, nutrition, and cancer has emphasized both etiology and public health implications, and has integrated biochemical and molecular techniques. Dr. Ziegler received a B.A. in chemistry and English from Swarthmore College, a Ph.D. in biochemistry from the University of California at Berkeley, and a M.P.H. in epidemiology and public policy from the Harvard School of Public Health. She has developed and taught courses on public health nutrition, international nutrition, and global food resources at Yale, Harvard, and Tufts Universities. Dr. Ziegler helped establish the Nutritional Epidemiology Research Interest Section of the American Society of Nutritional Sciences and currently serves on the editorial boards of the Journal of the National Cancer Institute, the American Journal of Clinical Nutrition, and the Nutrition Action Healthletter. In 1996, she was awarded the NIH Merit Award for her research on the role of vegetables, fruits, and micronutrients in the etiology of cancer.

Selected Publications

  1. Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X, Sue LY, Buys SS, Isaacs C, Keefer LK, Veenstra TD, Berg CD, Hoover RN, Ziegler RG. Estrogen metabolism and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2012;104(4):326-39.

  2. GarcĂ­a-Closas M, Gail MH, Kelsey KT, Ziegler RG. Searching for blood DNA methylation markers of breast cancer risk and early detection. J Natl Cancer Inst. 2013;105(10):678-80.

  3. Weinstein SJ, Purdue MP, Smith-Warner SA, Mondul AM, Black A, Ahn J, Huang WY, Horst RL, Kopp W, Rager H, Ziegler RG, Albanes D. Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer. 2015;136(6):E654-64.

  4. Ziegler RG, Fuhrman BJ, Moore SC, Matthews CE. Epidemiologic studies of estrogen metabolism and breast cancer. Steroids. 2015;99(Pt A):67-75.

  5. Schairer C, Fuhrman BJ, Boyd-Morin J, Genkinger JM, Gail MH, Hoover RN, Ziegler RG. Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association. Cancer Epidemiol Biomarkers Prev. 2016;25(1):105-13.

This page was last updated on October 13th, 2016