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Mapping the complex paracrine response to hormones in the human breast at single-cell resolution

View ORCID ProfileLyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, 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.
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Joseph Caruso
3Department 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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Alexander D Borowsky
4Center for Comparative Medicine, University of California Davis, Davis CA 95696.
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Tejal A Desai
5Department 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
3Department 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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Abstract

The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy controls breast development and modifies cancer risk. How these hormones uniquely impact each cell type in the breast is not well understood, because many of their effects are indirect–only a fraction of cells express hormone receptors. Here, we use single-cell transcriptional analysis to reconstruct in silico trajectories of the response to cycling hormones in the human breast. We find that during the menstrual cycle, rising estrogen and progesterone levels drive two distinct paracrine signaling states in hormone-responsive cells. These paracrine signals trigger a cascade of secondary responses in other cell types, including an “involution” transcriptional signature, extracellular matrix remodeling, angiogenesis, and a switch between a pro- and anti-inflammatory immune microenvironment. We observed similar cell state changes in women using hormonal contraceptives. We additionally find that history of prior pregnancy alters epithelial composition, increasing the proportion of myoepithelial cells and decreasing the proportion of hormone-responsive cells. These results provide systems-level insight into the links between hormone cycling and breast cancer risk.

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Posted September 29, 2018.
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Mapping the complex paracrine response to hormones in the human breast at single-cell resolution
Lyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, 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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Mapping the complex paracrine response to hormones in the human breast at single-cell resolution
Lyndsay M Murrow, Robert J Weber, Joseph Caruso, Christopher S McGinnis, 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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