Estrogen exacerbates mammary involution through neutrophil dependent and independent mechanism

  1. Chew Leng Lim
  2. Yu Zuan Or
  3. Zoe Ong
  4. Hwa Hwa Chung
  5. Hirohito Hayashi
  6. Smeeta Shrestha
  7. Shunsuke Chiba
  8. Feng Lin
  9. Valerie Chun Ling Lin  Is a corresponding author
  1. Nanyang Technological University, Singapore
  2. Dayananda Sagar University, India

Abstract

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.

Data availability

Sequencing data have been deposited in DR-NTU (DATA) accessible with the URL https://doi.org/10.21979/N9/YBRINN.

The following data sets were generated

Article and author information

Author details

  1. Chew Leng Lim

    NTU Institute for Health Technologies, Interdisciplinary Graduate School; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4529-2732
  2. Yu Zuan Or

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Zoe Ong

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Hwa Hwa Chung

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Hirohito Hayashi

    Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Smeeta Shrestha

    School of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6560-4230
  7. Shunsuke Chiba

    Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Feng Lin

    School of Computer Science and Engineering, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Valerie Chun Ling Lin

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    For correspondence
    cllin@ntu.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7997-2771

Funding

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.

Reviewing Editor

  1. Yuting Ma, Suzhou Institute of Systems Medicine, China

Ethics

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.

Version history

  1. Received: March 26, 2020
  2. Accepted: July 23, 2020
  3. Accepted Manuscript published: July 24, 2020 (version 1)
  4. Version of Record published: August 10, 2020 (version 2)

Copyright

© 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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  1. Chew Leng Lim
  2. Yu Zuan Or
  3. Zoe Ong
  4. Hwa Hwa Chung
  5. Hirohito Hayashi
  6. Smeeta Shrestha
  7. Shunsuke Chiba
  8. Feng Lin
  9. Valerie Chun Ling Lin
(2020)
Estrogen exacerbates mammary involution through neutrophil dependent and independent mechanism
eLife 9:e57274.
https://doi.org/10.7554/eLife.57274

Share this article

https://doi.org/10.7554/eLife.57274

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