Abstract
BackgroundIn 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.MethodsWe 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.ResultsWe 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.ConclusionsAs 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.
Highlights
In utero endocrine disruption is linked to increased risk of breast cancer later in life
As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect Endocrine disrupting compound (EDC) exposures to molecular alterations associated with increased disease susceptibility
In utero bisphenol A (BPA) alters the transcriptome of fibroblasts in adult female mice Several studies have implicated the mesenchymal cells surrounding the developmental mammary bud as a target of in utero BPA action [14,15,16]
Summary
In utero endocrine disruption is linked to increased risk of breast cancer later in life. We investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. In utero exposure to estrogenic endocrine disruptors (EDCs) is associated with increased risk of breast cancer. The ability of BPA to act as an estrogen has raised concerns over these exposures, leading to its replacement in various commercial products. These BPA replacements have varying levels of estrogenic activity with compounds such as bisphenol AF having higher estrogenic activity than BPA and bisphenol S (BPS) having lower estrogenic activity [5,6,7]. As the number of EDCs expands, understanding the critical properties and mechanisms driving risk becomes more imperative
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