Breast cancer in the multiethnic cohort study: Genetic (prolactin pathway genes) and environmental (hormone therapy) factors.

摘要

Both genetic and environmental factors may contribute to the risk of breast cancer. In this dissertation, using a novel haplotype-based approach, common genetic variation in the prolactin (PRL) and prolactin receptor (PRLR) genes is assessed in relation to plasma PRL levels and breast cancer risk among African-American, Hawaiian, Japanese, Latina, and White women in the Multiethnic Cohort Study (MEC). Animal studies and human in vitro studies suggest that PRL is involved in breast development and tumorigenesis, and the largest prospective cohort study of postmenopausal women found a 34% increase in risk of breast cancer when comparing women among the top to bottom quartiles of plasma PRL levels. However, no study has yet evaluated the possible role of common genetic variation in PRL pathway genes and breast cancer risk, or their potential contribution in determining circulating PRL levels.; This dissertation also examines the role of postmenopausal hormone therapy (HT), a widely prescribed treatment for menopausal symptoms, and its association with breast cancer risk. Both observational studies and results from the Women's Health Initiative trial indicate that HT use, specifically combined estrogen-progestin therapy (EPT) use, is associated with an overall increase in breast cancer risk. However, further data are needed on whether this association varies by factors such as stage of disease, weight, histologic subtype, schedule of progestin administration, and hormone receptor status, and no study has yet evaluated ethnic-specific differences in risk associated with HT use. The role of HT use and breast cancer risk is evaluated, first, in a meta-analysis of the existing published literature on EPT use and breast cancer risk and second, in a prospective cohort study of HT use and breast cancer risk among postmenopausal women in MEC.; These two areas of research, haplotype-based analyses of disease susceptibility genes and studies of HT use and breast cancer risk, address current issues in breast cancer research and contribute to a greater understanding of the complex etiology of breast cancer. By evaluating these factors among a multiethnic population, we address whether the association between these genetic and lifestyle factors and breast cancer risk vary by race/ethnicity.