Abstract
BACKGROUND: Biologic pathways underlying the association between outdoor air pollution and breast cancer risk are poorly understood. Breast tissue composition may reflect cumulative exposure to breast cancer risk factors and has been associated with breast cancer risk among patients with benign breast disease. Herein, we evaluated whether fine particulate matter (PM(2.5)) was associated with the histologic composition of normal breast tissue. METHODS: Machine-learning algorithms were applied to digitized hematoxylin and eosin-stained biopsies of normal breast tissue to quantify the epithelium, stroma, adipose and total tissue area from 3,977 individuals aged 18-75 years from a primarily Midwestern United States population who donated breast tissue samples to the Susan G. Komen Tissue Bank (2009-2019). Annual levels of PM(2.5) were assigned to each woman's residential address based on year of tissue donation. We applied predictive k-means to assign participants to clusters with similar PM(2.5) chemical composition and used linear regression to examine the cross-sectional associations between a 5-μg/m(3) increase in PM(2.5) and square root-transformed proportions of epithelium, stroma, adipose, and epithelium-to-stroma proportion [ESP], overall and by PM(2.5) cluster. RESULTS: Higher residential PM(2.5) was associated with lower proportion of breast stromal tissue [β = -0.93, 95% confidence interval: (-1.52, -0.33)], but was not related to the proportion of epithelium [β = -0.11 (-0.34, 0.11)]. Although PM(2.5) was not associated with ESP overall [β = 0.24 (-0.16, 0.64)], the association significantly differed by PM(2.5) chemical composition (p-interaction = 0.04), with a positive association evident only among an urban, Midwestern cluster with higher concentrations of nitrate (NO(3)(-)) and ammonium (NH(4)(+)) [β = 0.49 (0.03, 0.95)]. CONCLUSIONS: Our findings are consistent with a possible role of PM(2.5) in breast cancer etiology and suggest that changes in breast tissue composition may be a potential pathway by which outdoor air pollution impacts breast cancer risk. This study further underscores the importance of considering heterogeneity in PM(2.5) composition and its impact on breast carcinogenesis.