Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution

Lyndsay M Murrow; Robert J Weber; Joseph A Caruso; Christopher S McGinnis; Kiet Phong; Philippe Gascard; Gabrielle Rabadam; Alexander D Borowsky; Tejal A Desai; Matthew Thomson; Thea Tlsty; Zev J Gartner

doi:10.1016/j.cels.2022.06.005

Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution

Cell Syst. 2022 Aug 17;13(8):644-664.e8. doi: 10.1016/j.cels.2022.06.005. Epub 2022 Jul 20.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lmurrow@gmail.com.
² Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Medical Scientist Training Program (MSTP), University of California, San Francisco, San Francisco, CA 94518, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Pathology and Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Center for Immunology and Infectious Diseases, Department of Pathology and Laboratory Medicine, University of California, Davis, Davis, CA 95696, USA.
⁷ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Computational Biology, Caltech, Pasadena, CA 91125, USA.
⁹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: zev.gartner@ucsf.edu.

Abstract

The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy regulates breast development and modifies cancer risk. How these hormones impact each cell type in the breast remains poorly understood because they act indirectly through paracrine networks. Using single-cell analysis of premenopausal breast tissue, we reveal a network of coordinated transcriptional programs representing the tissue-level response to changing hormone levels. Our computational approach, DECIPHER-seq, leverages person-to-person variability in breast composition and cell state to uncover programs that co-vary across individuals. We use differences in cell-type proportions to infer a subset of programs that arise from direct cell-cell interactions regulated by hormones. Further, we demonstrate that prior pregnancy and obesity modify hormone responsiveness through distinct mechanisms: obesity reduces the proportion of hormone-responsive cells, whereas pregnancy dampens the direct response of these cells to hormones. Together, these results provide a comprehensive map of the cycling human breast.

Keywords: cell-cell interactions; hormone signaling; human breast; sample heterogeneity; scRNA-seq; single-cell genomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Breast* / metabolism
Cell Communication
Estrogens / metabolism
Female
Humans
Obesity / metabolism
Pregnancy
Progesterone* / metabolism

Substances

Estrogens
Progesterone

Abstract

Publication types

MeSH terms

Substances

Grants and funding