Air Pollution in Relation to Mammographic Density, Breast Cancer Survival, and Breast Tissue Gene Expression

Abstract

Ambient air pollution and particulate matter (PM) are Group 1 human carcinogens and induce systemic effects relevant to carcinogenesis. Breast cancer is the most diagnosed cancer, excluding non-melanoma skin cancer, and the leading cause of cancer death among women worldwide. While air pollution is largely not associated with breast cancer incidence, its role on other breast outcomes is limited. This thesis investigated associations between air pollution and other breast outcomes in the Nurses’ Health Study (NHS) and NHSII. PM exposures (PM2.5, PM2.5-10, PM10) were estimated using spatio-temporal models linked to participants’ residential addresses. Mammographic density was measured in participants without breast cancer. Self-reported breast cancer diagnoses were confirmed by medical record review and information on cause of death was ascertained. Among women with breast cancer, archival breast tissue specimens were collected to obtain global gene expression data. We used linear regression models to estimate differences in mammographic density and Cox proportional hazards models to estimate Hazard Ratios (HR) with increasing PM. Gene set enrichment analyses and the least squares kernel machine were conducted to identify gene expression pathways associated with PM2.5. PM exposures were not associated with mammographic density in pre- and post-menopausal women, though there was a suggestive association among post-menopausal women residing in the Northeast where mammographic density was higher by 3.4 percentage points (95% CI -0.5, 7.3) for a 10 µg/m3 increase in PM2.5. Across Stage I-III breast cancer participants, increases in PM were not associated with breast-cancer specific mortality (PM2.5: HR=1.09 95% CI 0.87, 1.36). However, among participants with Stage I disease, a 10 μg/m3 increase in PM2.5 was associated with higher breast-cancer specific mortality (HR=1.64 95% CI 1.11, 2.43) and was associated with expression of oxidative phosphorylation in adjacent-normal breast tissue. Overall, PM exposures were not associated with breast outcomes; however, several subgroup findings suggest that PM2.5 may influence the breast tissue. Specifically, PM2.5 was associated with higher mammographic density in post-menopausal women residing in the Northeast, higher breast-cancer specific mortality among those with Stage I disease, and with perturbations of the oxidative phosphorylation pathway in the adjacent-normal tissue of women with Stage 1 disease.