Abstract

Over half of breast cancer related deaths are due to recurrence five or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

Data availability

Sequencing data have been deposited in SRA as PRJNA506006 for cell line data and PRJNA505845 for macrophage data.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Andrea Walens

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    For correspondence
    andrea.walens@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Ashley V DiMarco

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan Lupo

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin R Kroger

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffrey S Damrauer

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8148-0285
  6. James V Alvarez

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    For correspondence
    james.alvarez@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2910-7621

Funding

National Cancer Institute (F31 CA220957)

  • Andrea Walens

National Cancer Institute (R01 CA208042)

  • James V Alvarez

Duke University School of Medicine

  • James V Alvarez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Päivi M Ojala, University of Helsinki, Finland

Ethics

Animal experimentation: All animal experiments were performed with approval from the Duke institutional animal care and use committee (IACUC) under Protocol #A199-17-08 and in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Mice were housed under barrier conditions with standard 12-hour light/dark hours, and fed standard chow.

Version history

  1. Received: November 14, 2018
  2. Accepted: March 27, 2019
  3. Accepted Manuscript published: April 16, 2019 (version 1)
  4. Version of Record published: April 23, 2019 (version 2)

Copyright

© 2019, Walens 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. Andrea Walens
  2. Ashley V DiMarco
  3. Ryan Lupo
  4. Benjamin R Kroger
  5. Jeffrey S Damrauer
  6. James V Alvarez
(2019)
CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors
eLife 8:e43653.
https://doi.org/10.7554/eLife.43653

Share this article

https://doi.org/10.7554/eLife.43653

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