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Pregnancy and obesity modify the epithelial composition and hormone signaling state of the human breast

View ORCID ProfileLyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, Philippe Gascard, Alexander D Borowsky, Tejal A Desai, Matthew Thomson, Thea Tlsty, Zev J Gartner
doi: https://doi.org/10.1101/430611
Lyndsay M Murrow
1Department of Pharmaceutical Chemistry and Center for Cellular Construction, University of California San Francisco, San Francisco CA 94158
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  • ORCID record for Lyndsay M Murrow
Robert J Weber
1Department of Pharmaceutical Chemistry and Center for Cellular Construction, University of California San Francisco, San Francisco CA 94158
2Medical Scientist Training Program (MSTP), University of California, San Francisco, San Francisco, California, USA
3Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158
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Joseph Caruso
4Department of Pathology and Helen Diller Cancer Center, University of California San Francisco, San Francisco CA 94143
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Christopher S McGinnis
1Department of Pharmaceutical Chemistry and Center for Cellular Construction, University of California San Francisco, San Francisco CA 94158
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Philippe Gascard
4Department of Pathology and Helen Diller Cancer Center, University of California San Francisco, San Francisco CA 94143
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Alexander D Borowsky
5Center for Immunology and Infectious Diseases, Department of Pathology and Lab, University of California Davis, Davis CA 95696
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Tejal A Desai
3Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158
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Matthew Thomson
6Computational Biology, Caltech, Pasadena CA 91125
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Thea Tlsty
4Department of Pathology and Helen Diller Cancer Center, University of California San Francisco, San Francisco CA 94143
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Zev J Gartner
1Department of Pharmaceutical Chemistry and Center for Cellular Construction, University of California San Francisco, San Francisco CA 94158
7Chan Zuckerberg Biohub, University of California San Francisco, San Francisco CA 94158
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  • For correspondence: zev.gartner@ucsf.edu
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Summary

Reproductive history and body weight are two important breast cancer risk factors. Prior pregnancy (parity) reduces lifetime risk by up to 50%, and obesity reduces premenopausal risk by up to 45%. Here, we use single-cell RNA sequencing to directly link these risk factors with tumor-protective changes in epithelial cell proportions and hormone signaling in the premenopausal breast. We show that parity reduces the proportion of transformation-susceptible luminal cells and increases the proportion of tumor-suppressive myoepithelial cells in the epithelium. Additionally, we identify two distinct mechanisms by which parity and obesity contribute to reduced hormone signaling. First, parity reduces the per-cell transcriptional response to ovarian hormones in hormone-responsive cells. Second, parity and obesity reduce the overall proportion of hormone-responsive cells. Both mechanisms lead to a decreased paracrine signaling response in myoepithelial cells. Together these findings provide mechanistic insight into how BMI and parity affect the mammary epithelial microenvironment to modify breast cancer susceptibility.

Footnotes

  • This version of the manuscript represents our updated findings based on sequencing 19 additional samples, for a total of 28 samples. All figures and text have been substantially revised.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 13, 2020.
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Pregnancy and obesity modify the epithelial composition and hormone signaling state of the human breast
Lyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, Philippe Gascard, Alexander D Borowsky, Tejal A Desai, Matthew Thomson, Thea Tlsty, Zev J Gartner
bioRxiv 430611; doi: https://doi.org/10.1101/430611
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Pregnancy and obesity modify the epithelial composition and hormone signaling state of the human breast
Lyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, Philippe Gascard, Alexander D Borowsky, Tejal A Desai, Matthew Thomson, Thea Tlsty, Zev J Gartner
bioRxiv 430611; doi: https://doi.org/10.1101/430611

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