Murrow, Lyndsay M. and Weber, Robert J. and Caruso, Joseph A. 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 (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200121-074722672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) | ||||||||||||||||||||
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| 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, Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks | ||||||||||||||||||||
| Additional Information: | The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. History: Version 1 - September 29, 2018; Version 2 - March 13, 2020; Version 3 - October 21, 2020; Version 4 - November 25, 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.A.C., R.J.W., C.S.M., and K.P. performed the sequencing experiments. C.S.M. generated aligned reads and barcode matrices. C.S.M and L.M.M. performed sample demultiplexing. P.G. coordinated sample acquisition and provided critical guidance for sample selection. L.M.M. performed fluorescent immunohistochemistry and RNA-FISH experiments. L.M.M. and J.A.C. performed flow cytometry experiments. L.M.M. performed histopathology on tissue sections. A.D.B. performed histopathological tissue analysis. L.M.M. analyzed and visualized the data. M.T. provided guidance in data analyses and computational approaches. T.T. and A.D.B. provided 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. Data availability: Submission of raw gene expression and barcode count matrices to the Gene Expression Omnibus is in process. For inquiries about data, code, or materials, contact authors. The authors have declared no competing interest. | ||||||||||||||||||||
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| Subject Keywords: | mammary gland, single-cell RNA sequencing, menstrual cycle, parity, pregnancy history, hormone signaling, breast cancer risk | ||||||||||||||||||||
| DOI: | 10.1101/430611 | ||||||||||||||||||||
| 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: | 16 Nov 2021 17:57 |
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