CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors
- Duke University, United States
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.
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Tumor associated macrophage sequencing from primary, regressing, and recurrent MTB;TAN tumors.NCBI Sequence Read Archive, PRJNA505845.
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Changes in gene expression after Her2 down regulationNCBI Sequence Read Archive, PRJNA506006.
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Letrozole (Femara) early response to treatmentNCBI Gene Expression Omnibus, GSE10281.
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Molecular Subtype Predicts Response to Neoadjuvant Chemotherapy in Breast CancerNCBI Gene Expression Omnibus, GSE21974.
Article and author information
Author details
Jeffrey S Damrauer
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.
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.
Reviewing Editor
- Päivi M Ojala, University of Helsinki, Finland
Version history
- Received: November 14, 2018
- Accepted: March 27, 2019
- Accepted Manuscript published: April 16, 2019 (version 1)
- 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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CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors
eLife 8:e43653.
https://doi.org/10.7554/eLife.43653
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