Author:
Wormsbaecher Clarissa,Hindman Andrea R.,Avendano Alex,Cortes-Medina Marcos,Jones Caitlin E.,Bushman Andrew,Onua Lotanna,Kovalchin Claire E.,Murphy Alina R.,Helber Hannah L.,Shapiro Ali,Voytovitch Kyle,Kuang Xingyan,Aguilar-Valenzuela Renan,Leight Jennifer L.,Song Jonathan W.,Burd Craig J.
Abstract
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Funder
National Science Foundation
Pelotonia
National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Cited by
22 articles.
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