Estrogen exacerbates mammary involution through neutrophil dependent and independent mechanism
There is strong evidence that the pro-inflammatory microenvironment during post-partum mammary involution promotes parity-associated breast cancer. Estrogen exposure during mammary involution drives tumour growth through neutrophils' activity. However, how estrogen and neutrophils influence mammary involution are unknown. Combined analysis of transcriptomic, protein, and immunohistochemical data in BALB/c mice showed that estrogen promotes involution by exacerbating inflammation, cell death and adipocytes repopulation. Remarkably, 88% of estrogen-regulated genes in mammary tissue were mediated through neutrophils, which were recruited through estrogen-induced CXCR2 signalling in an autocrine fashion. While neutrophils mediate estrogen-induced inflammation and adipocytes repopulation, estrogen-induced mammary cell death was via lysosome-mediated programmed cell death through upregulation of cathepsin B, Tnf and Bid in a neutrophil-independent manner. Notably, these multifaceted effects of estrogen are mostly mediated by ERα and unique to the phase of mammary involution. These findings are important for the development of intervention strategies for parity-associated breast cancer.
Sequencing data have been deposited in DR-NTU (DATA) accessible with the URL https://doi.org/10.21979/N9/YBRINN.
RNA-sequencing data of Balb/c involuting mammary gland treated with anti-Ly6G antibody and estrogenDR-NTU (DATA), 10.21979/N9/YBRINN.
Article and author information
Ministry of Education of Singapore (MOE2017-T1-002-08)
- Valerie Chun Ling Lin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were performed in accordance with the protocol approved by the Nanyang Technological University Institutional Animal Care and Use Committee (NTU-IACUC) under the protocol number A0306 and A18036.
- Yuting Ma, Suzhou Institute of Systems Medicine, China
- Received: March 26, 2020
- Accepted: July 23, 2020
- Accepted Manuscript published: July 24, 2020 (version 1)
- Version of Record published: August 10, 2020 (version 2)
© 2020, Lim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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