The molecular consequences of androgen activity in the human breast

Florian Raths; Mehran Karimzadeh; Nathan Ing; Andrew Martinez; Yoona Yang; Ying Qu; Tian-Yu Lee; Brianna Mulligan; Suzanne Devkota; Wayne T Tilley; Theresa E Hickey; Bo Wang; Armando E Giuliano; Shikha Bose; Hani Goodarzi; Edward C Ray; Xiaojiang Cui; Simon R V Knott

doi:10.1016/j.xgen.2023.100272

The molecular consequences of androgen activity in the human breast

Cell Genom. 2023 Mar 8;3(3):100272. doi: 10.1016/j.xgen.2023.100272.

Authors

Florian Raths^{1

2}, Mehran Karimzadeh^{3

4

5

6

7

8}, Nathan Ing^{1

2}, Andrew Martinez^{1

2}, Yoona Yang^{1

2}, Ying Qu⁹, Tian-Yu Lee⁹, Brianna Mulligan^{1

2}, Suzanne Devkota^{2

10}, Wayne T Tilley^{11

12}, Theresa E Hickey¹¹, Bo Wang^{4

5

13

14}, Armando E Giuliano⁹, Shikha Bose¹⁵, Hani Goodarzi^{3

6

7

8}, Edward C Ray^{9

16}, Xiaojiang Cui⁹, Simon R V Knott^{1

2}

Affiliations

¹ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁴ Vector Institute, Toronto, ON, Canada.
⁵ Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
⁶ Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹¹ Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
¹² Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, Australia.
¹³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁶ Transgender Surgery and Health Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Abstract

Estrogen and progesterone have been extensively studied in the mammary gland, but the molecular effects of androgen remain largely unexplored. Transgender men are recorded as female at birth but identify as male and may undergo gender-affirming androgen therapy to align their physical characteristics and gender identity. Here we perform single-cell-resolution transcriptome, chromatin, and spatial profiling of breast tissues from transgender men following androgen therapy. We find canonical androgen receptor gene targets are upregulated in cells expressing the androgen receptor and that paracrine signaling likely drives sex-relevant androgenic effects in other cell types. We also observe involution of the epithelium and a spatial reconfiguration of immune, fibroblast, and vascular cells, and identify a gene regulatory network associated with androgen-induced fat loss. This work elucidates the molecular consequences of androgen activity in the human breast at single-cell resolution.

Keywords: androgen regulation of human breast homeostasis; breast microenvironment; cellular metabolism; chromatin regulation; hormone receptor; lactation; multiplexed immunohistochemistry by co-detection by indexing; single-cell ATAC sequencing; single-cell RNA sequencing; transcriptional control.

Abstract

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