Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers
- Ken Takai1,2,
- Allison P. Drain3,
- Devon A. Lawson1,6,
- Laurie E. Littlepage1,7,
- Marcela Karpuj1,8,
- Kai Kessenbrock1,9,
- Annie Le1,
- Kenichi Inoue2,
- Valerie M. Weaver3,4,5 and
- Zena Werb1
- 1Department of Anatomy, University of California at San Francisco, San Francisco, California 94143, USA;
- 2Division of Breast Oncology, Saitama Cancer Center, Saitama 362-0806, Japan;
- 3Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California at San Francisco, San Francisco, California 94143, USA;
- 4Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, California 94143, USA;
- 5Department of Radiation Oncology, University of California at San Francisco, San Francisco, California 94143, USA
- Corresponding author: zena.werb{at}ucsf.edu
Abstract
The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1+/+ mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1−/− mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1−/− mice and higher branching by their isolated organoids. When we crossed DDR1−/− mice with MMTV-PyMT mice, the PyMT/DDR1−/− mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90+CD24+ cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14+ basal cells, including K8+K14+ cells, were increased adjacent to necrotic fields. These data suggest that the absence of DDR1 provides a growth and adhesion advantage that favors the expansion of basal cells, potentiates fibrosis, and enhances necrosis/hypoxia and basal differentiation of transformed cells to increase their aggression and metastatic potential.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.301366.117.
- Received May 2, 2017.
- Accepted January 24, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.