Neighborhood Environment, DNA Methylation, and Presence of Crown-Like Structures of the Breast
Authors: Alexandra R. Harris, Jeri D. Hughes, Wayne R. Lawrence, Petra Lenz, Jamirra Franklin, Praphulla M. S. Bhawsar, Tiffany H. Dorsey, Emily L. Rossi, Catherine M. Pichardo, Margaret S. Pichardo, Alexandra J. White, Cody Ramin, Máire A. Duggan, Mustapha Abubakar, Aaron M. Rozeboom, Jonas S. Almeida, Gretchen L. Gierach, Stefan Ambs, Brittany D. Jenkins
Journal: JAMA Network Open (2025)

Importance Inflammation impacts cancer risk and tumor biological processes, yet studies linking it to social and environmental risk factors are lacking. Objective To investigate the association of neighborhood deprivation and air pollution with breast adipose inflammation as well as the association between crown-like structures of the breast (CLS-B) and DNA methylation in Black and White women. Design, Setting, and Participants This cross-sectional study analyzed women with and without breast cancer participating in the National Cancer Institute–Maryland Breast Cancer Study, most of whom were recruited between January 1, 1993, and December 1, 2003, from the University of Maryland Medical Center and surrounding hospitals in the Baltimore, Maryland, area. A small subset of the sample was recruited between March 27, 2012, and November 27, 2017. Noncancerous breast tissue was collected from women who underwent reduction mammoplasty or breast cancer surgery. Statistical analyses were conducted between May and August 2024. Exposures Two socioenvironmental exposures were examined: air pollution (specifically, fine particulate matter less than 2.5 μm in diameter [PM 2.5 ]) and neighborhood deprivation (measured with Neighborhood Deprivation Index [NDI]). Participant geocodes were linked to 2000 US Census data to calculate PM 2.5 concentrations (total mass [μg/m 3 ]) and NDI. Main Outcomes and Measures Breast tissues underwent immunohistochemical staining for pan-macrophage marker CD68 to detect 2 outcomes: CLS-B and adipose-associated macrophages. CLS-B and adipose-related macrophages were assessed by pathologists using artificial intelligence–assisted and manual approaches. Covariate-adjusted logistic regression models were used to ascertain associations between PM 2.5 and NDI (exposures) and presence or absence of CLS-B (outcome); CD68-positive adipose macrophages were modeled as a dichotomous high or low variable. Covariate-adjusted linear regression was used to identify associations between CLS-B (exposure) and DNA methylation (outcome). Results The cohort included 205 participants (127 Black [62.0%], 78 White [38.0%] women; mean [SD] age, 48.7 [13.3] years). Women with vs without CLS-B had higher median (IQR) body mass index (calculated as weight in kilograms divided by height in meters squared; 35.5 [30.5-40.9] vs 31.8 [26.6-36.4]; P = .02). Higher levels of PM 2.5 (odds ratio [OR], 2.32; 95% CI, 1.12-4.78; P = .02) and NDI (OR, 1.21; 95% CI, 1.02-1.43; P = .03) were associated with presence of CLS-B overall; findings were still significant among Black women (PM 2.5 : OR, 2.64 [95% CI, 1.10-6.33], P = .03; NDI: OR, 1.22 [95% CI, 1.01-1.48], P = .04) but were not statistically significant among White women (PM 2.5 : OR, 1.65 [95% CI, 0.45-5.99], P = .45; NDI: OR, 1.19 [95% CI, 0.83-1.70], P = .35). Higher PM 2.5 concentration was associated with increased macrophage infiltration (OR, 2.11; 95% CI, 1.24-3.60; P = .006), with similar outcomes by race. The top 2 significant differentially methylated CpG sites by CLS-B status were SAR1B (β = 0.01; 95% CI, 0.01-0.02; P &amp;amp;lt; .001) and IL2RB (β = −0.04; 95% CI, −0.05 to −0.02; P &amp;amp;lt; .001). Significant interaction was observed between CLS-B status and race for IL2RB methylation levels (β = −0.03; 95% CI, −0.04 to −0.01; P for interaction &amp;amp;lt;.001). Conclusions and Relevance This cross-sectional study uncovered an association between neighborhood-level social and environmental risk factors and breast tissue inflammation. The findings help inform efforts to reduce racial and socioeconomic disparities in breast cancer and improve health equity for socially vulnerable populations.