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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

Open Access 01-12-2020 | Breast Cancer | Research article

In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness

Authors: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Caitlin E. Jones, Andrew Bushman, Lotanna Onua, Claire E. Kovalchin, Alina R. Murphy, Hannah L. Helber, Ali Shapiro, Kyle Voytovitch, Xingyan Kuang, Renan Aguilar-Valenzuela, Jennifer L. Leight, Jonathan W. Song, Craig J. Burd

Published in: Breast Cancer Research | Issue 1/2020

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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.
Appendix
Available only for authorised users
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Metadata
Title
In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness
Authors
Clarissa Wormsbaecher
Andrea R. Hindman
Alex Avendano
Marcos Cortes-Medina
Caitlin E. Jones
Andrew Bushman
Lotanna Onua
Claire E. Kovalchin
Alina R. Murphy
Hannah L. Helber
Ali Shapiro
Kyle Voytovitch
Xingyan Kuang
Renan Aguilar-Valenzuela
Jennifer L. Leight
Jonathan W. Song
Craig J. Burd
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01275-w

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