From The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden HORMONE-RELATED DIETARY FACTORS AND ESTROGEN / PROGESTERONE-RECEPTOR DEFINED POSTMENOPAUSAL BREAST CANCER

Breast cancer is the most common invasive cancer among women in Western countries including Sweden. It has been hypothesized that ovarian hormones, such as estrogen and progesterone may, at least partly, play an important role in the etiology of breast cancer. Several nutritional related factors alcohol, body weight, dietary fiber, and dietary lignans are postulated to affect levels of estrogen, progesterone and/or insulin and to be associated with the development/prevention of breast cancer through hormonal modulation. Evidence from in vitro, in vivo and from observational studies suggested an association between these dietary factors and the risk of breast cancer. However, it is not fully defined whether the major underlying mechanisms of the association between these factors and breast cancer are hormone-dependent or not. The aim of this thesis was to investigate the relation between these hormone-related nutritional factors, such as alcohol, body weight, dietary fiber, and dietary lignans, and invasive breast cancer incidence with estrogenprogesteronereceptor (ER/PR) status in the population-based prospective Swedish Mammography Cohort (SMC). The SMC includes women born between 1914 and 1948 and living in Uppsala and Vastmanland Counties who received a mailed questionnaire (1987 90) and a follow-up questionnaire (1997). Our analyses include 51 823 postmenopausal women in the SMC who were cancer free and completed the questionnaire at baseline. Cox proportional hazard models were used to estimate rate ratios (RRs) with 95% confidence intervals (CIs) with adjustment for potential confounders. All statistical tests were two-sided. From March 1987 through June 2004, 1,188 invasive breast cancer patients with known ER/PR status were identified. Among them, 716 were ER+PR+, 279 were ER+PR , 50 were ER PR+, and 143 were ER PR . Alcohol intake was positively associated with the risk of breast cancer, especially with ER+ tumors and the observed associations were more pronounced among PMH users. Body weight was positively associated with the development of ER+PR+ tumors, but not with other tumors subtypes. This positive association was confined to PMH neverusers. We observed non-significant inverse association of total dietary fiber with all types of tumors. However, we observed statistically significant inverse associations confined to women without family history of breast cancer, to PMH ever-users, and to those with high alcohol consumption. Fruit fiber intake was inversely associated with the risk of all breast cancer, especially among PMH never-users. In contrast, among PMH everusers, cereal fiber intake was inversely associated with the risk of ER+PR+ tumors. We observed non-significant inverse association of dietary lignans with all breast cancer risk. In a similar manner as cereal fiber intake, dietary lignans were inversely associated with the risk of ER+PR+ tumors among PMH ever-users. In conclusion, our findings from this large prospective cohort suggest that alcohol, body weight, dietary fiber and lignans intake could partly affect the risk of postmenopausal breast cancer through hormone dependent mechanisms. Our results indicate that the choice of diet rich in dietary fiber and low alcohol consumption and body weight control are important factors for the prevention of postmenopausal breast cancer, especially among PMH ever-users. In evaluating the association between hormone-related nutritional factors and the risk of postmenopausal breast cancer, the tumors’ ER/PR status should be considered. LIST OF PUBLICATIONS I. Reiko Suzuki, Weimin Ye, Tove Rylander-Rudqvist, Shigehira Saji, Graham A Colditz, Alicja Wolk. Alcohol and Postmenopausal Breast Cancer Risk Defined by Estrogen and Progesterone Receptor Status: A Prospective Cohort Study. Journal of the National Cancer Institute 2005; 97:1601 1608. II. Reiko Suzuki, Tove Rylander-Rudqvist, Weimin Ye, Shigehira Saji, Alicja Wolk. Body weight and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women: A prospective cohort study International Journal of Cancer 2006;119:1683 1689. III. Reiko Suzuki, Tove Rylander-Rudqvist, Weimin Ye, Shigehira Saji, Herman Adlercreutz, Alicja Wolk. Dietary Fiber Intake and Postmenopausal Breast Cancer Risk Defined by Estrogen and Progesterone Receptor Status A Prospective Cohort Study among Swedish Women (Submitted 2006) IV. Reiko Suzuki, Tove Rylander-Rudqvist, Shigehira Saji, Leif Bergkvist, Herman Adlercreutz, Alicja Wolk. Dietary lignans and Postmenopausal Breast Cancer Risk Defined by Estrogen and Progesterone Receptor Status A Prospective Cohort Study of Swedish Women (Manuscript 2006) CONTENTS