Lifestyle, Hormones, and Breast Cancer

Abstract

Breast cancer is a leading cause of cancer and the second leading cause of cancer death among women in the US. Although many risk factors for breast cancer are known, few are modifiable and little is known about ways to prevent its incidence. Early-life body size is inversely associated with both premenopausal and postmenopausal breast cancer risk, suggesting an excess risk in lean girls. In a prospective analysis within the Nurses’ Health Study (NHS) II, Chapter 1 examines whether adolescent physical activity mitigates the excess risk of breast cancer associated with early-life body leanness. Lean girls were at higher risk of breast cancer, regardless of the level of adolescent physical activity; however, the association was slightly, though not significantly, attenuated among the most active girls. Breast cancer is hormone-related cancer; estrogen metabolites (EM) are both estrogenic and genotoxic, suggesting factors that alter the pattern of estrogen metabolism may contribute to breast carcinogenesis. With the application of advanced technology that measures 15 different individual estrogens and EM in urine, Chapter 2 examines the associations of dietary fiber and macronutrients intake with detailed estrogen metabolism in a cross-sectional analysis within the NHSII. Few significant associations were identified: a positive association between total fiber intake and 4-methoxyestradiol, an inverse association between total fiber intake and 17-epiestriol, and inverse associations for polyunsaturated and trans-fat intakes with 17-epiestriol. The tissue-specific responsiveness to potentially carcinogenic hormones, estrogen and progesterone, is partially regulated by the tissue expression of receptors that bind these hormones. Using benign breast biopsy samples collected in a nested case-control study within the NHS and NHSII, Chapter 3 assesses estrogen receptor (ER), progesterone receptor (PR), and proliferative marker Ki67 expression in normal breast tissue in relation to subsequent breast cancer risk. In this case-control analysis, PR expression in normal breast tissue was significantly positively associated with breast cancer risk in premenopausal women. ER and Ki67 expression was not significantly associated with breast cancer risk; however, our power was limited. Results of this dissertation help elucidate the underlying biologic mechanisms of breast cancer and enhance our understanding of the link between risk factors and breast cancer risk.