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Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

Murrow, Lyndsay M. and Weber, Robert J. and Caruso, Joseph and McGinnis, Christopher S. and Phong, Kiet and Gascard, Philippe and Borowsky, Alexander D. and Desai, Tejal A. and Thomson, Matthew and Tlsty, Thea and Gartner, Zev J. (2018) Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200121-074722672

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Abstract

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/430611DOIDiscussion Paper
ORCID:
AuthorORCID
Murrow, Lyndsay M.0000-0002-5935-8977
Alternate Title:Mapping the complex paracrine response to hormones in the human breast at single-cell resolution, Pregnancy and obesity modify the epithelial composition and hormone signaling state of the human breast
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. bioRxiv preprint first posted online Sep. 29, 2018. History March 13, 2020. We thank Drs. Tom Norman and Jonathan Weissman for technical support and for generously providing access to equipment and computing resources. Sequencing was performed in the Center for Advanced Technology at UCSF. Tissue samples were provided by the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Samples from the Susan G. Komen Tissue Bank at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, as well as donors and their families, whose help and participation made this work possible. This research was supported in part by grants from the Department of Defense Breast Cancer Research Program (W81XWH-10-1-1023 and W81XWH-13-1-0221), NIH (U01CA199315 and DP2 HD080351-01), the NSF (MCB-1330864), and the UCSF Center for Cellular Construction (DBI-1548297), an NSF Science and Technology Center, to Z.J.G. Z.J.G is a Chan-Zuckerberg BioHub Investigator. L.M.M is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2239-15). Author Contributions: L.M.M., R.J.W., and Z.J.G. conceived the project. L.M.M., J.C., R.J.W., C.S.M., and K.P. performed the sequencing experiments. C.S.M. generated aligned reads and barcode matrices, and performed sample demultiplexing. P.G. and J.C. coordinated sample acquisition and provided critical guidance for sample selection. P.G. and J.C. performed sectioning for fluorescent immunohistochemistry experiments. L.M.M. performed fluorescent immunohistochemistry and RNA-FISH experiments. L.M.M. and J.C. performed flow cytometry experiments. A.D.B. performed histopathology on tissue sections. L.M.M. analyzed and visualized the data. M.T. provided critical guidance in data analyses and computational approaches. T.T. and A.D.B. provided critical guidance in human breast biology. T.T., M.T., and Z.J.G. provided critical resources. T.A.D., M.T., T.T., and Z.J.G. supervised the project. L.M.M. and Z.G. wrote the manuscript. All authors reviewed and edited the manuscript. REVISION SUMMARY: 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.
Funders:
Funding AgencyGrant Number
Department of DefenseW81XWH-10-1-1023
Department of DefenseW81XWH-13-1-0221
NIHU01CA199315
NIHDP2 HD080351-01
NSFMCB-1330864
NSFDBI-1548297
Chan-Zuckerberg BiohubUNSPECIFIED
Damon Runyon Cancer Research FoundationDRG-2239-15
Subject Keywords:mammary gland, single-cell RNA sequencing, menstrual cycle, parity, pregnancy history, hormone signaling, breast cancer risk
Record Number:CaltechAUTHORS:20200121-074722672
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200121-074722672
Official Citation: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 D Tlsty, Zev Jordan Gartner bioRxiv 430611; doi: https://doi.org/10.1101/430611
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100804
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jan 2020 18:02
Last Modified:21 Oct 2020 22:32

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