In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness
Open Access
- 5 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Breast Cancer Research
- Vol. 22 (1), 1-12
- https://doi.org/10.1186/s13058-020-01275-w
Abstract
In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.Keywords
Funding Information
- National Science Foundation (CBET-1752106)
- Pelotonia (NA, NA)
- National Science Foundation (EEC-185228)
- National Heart, Lung, and Blood Institute (R01HL141941-02S1)
This publication has 49 references indexed in Scilit:
- Low-Dose BPA Exposure Alters the Mesenchymal and Epithelial Transcriptomes of the Mouse Fetal Mammary GlandPLOS ONE, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Collagen‐agarose co‐gels as a model for collagen–matrix interaction in soft tissues subjected to indentationJournal of Biomedical Materials Research Part A, 2011
- Bisphenol A Increases Mammary Cancer Risk in Two Distinct Mouse Models of Breast CancerBiology of Reproduction, 2011
- Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor ProgressionCold Spring Harbor Perspectives in Biology, 2010
- Assessing Reproductive Status/Stages in MiceCurrent Protocols in Neuroscience, 2009
- ToppGene Suite for gene list enrichment analysis and candidate gene prioritizationNucleic Acids Research, 2009
- Collagen density promotes mammary tumor initiation and progressionBMC Medicine, 2008
- No effect of route of exposure (oral; subcutaneous injection) on plasma bisphenol A throughout 24h after administration in neonatal female miceReproductive Toxicology, 2008
- Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposureReproductive Toxicology, 2007