COX-2 modulates mammary tumor progression in response to collagen densityReport as inadecuate

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Breast Cancer Research

, 18:35

First Online: 22 March 2016Received: 12 November 2015Accepted: 03 March 2016DOI: 10.1186-s13058-016-0695-3

Cite this article as: Esbona, K., Inman, D., Saha, S. et al. Breast Cancer Res 2016 18: 35. doi:10.1186-s13058-016-0695-3


BackgroundHigh breast density is linked to an increased risk of breast cancer, and correlates with changes in collagen. In a mouse model of mammary carcinoma in the context of increased collagen deposition, the MMTV-PyMT-Col1a1, there is accelerated mammary tumor formation and progression. Previous gene expression analysis suggests that increased collagen density elevates expression of PTGS2 prostaglandin-endoperoxide synthase 2, the gene for cyclooxygenase-2 COX-2.

MethodsTo understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT-Col1a1 tumors prior to and after tumor formation. Animals received treatment with celecoxib, a specific COX-2 inhibitor, or placebo. Mammary tumors were examined for COX-2, inflammatory and stromal cell components, and collagen deposition through immunohistochemical analysis, immunofluorescence, multiplex cytokine ELISA and tissue imaging techniques.

ResultsPyMT-Col1a1 tumors were larger, more proliferative, and expressed higher levels of COX-2 and PGE2 than PyMT tumors in wild type WT mice. Treatment with celecoxib significantly decreased the induced tumor size and metastasis of the PyMT-Col1a1 tumors, such that their size was not different from the smaller PyMT tumors. Celecoxib had minimal effect on the PyMT tumors. Celecoxib decreased expression levels of COX-2, PGE2, and Ki-67. Several cytokines were over-expressed in PyMT-Col1a1 compared to PyMT, and celecoxib treatment prevented their over-expression. Furthermore, macrophage and neutrophil recruitment were enhanced in PyMT-Col1a1 tumors, and this effect was inhibited by celecoxib. Notably, COX-2 inhibition reduced overall collagen deposition. Finally, when celecoxib was used prior to tumor formation, PyMT-Col1a1 tumors were fewer and smaller than in untreated animals.

ConclusionThese findings suggest that COX-2 has a direct role in modulating tumor progression in tumors arising within collagen-dense microenvironments, and suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue and early-stage breast cancer.


CAFcancer-associated fibroblasts





ECMextracellular matrix

EGFepithelial growth factor

ELISAenzyme-linked immunosorbent assay

EMTepithelial-mesenchymal transition

FDAFood and Drug Administration


FFPEformalin-fixed paraffin embedding

FGFβfibroblast growth factor beta

G-CSFgranulocyte-colony stimulating factor CSF-2

GM-CSFgranulocyte-macrophage colony-stimulating factor CSF-3

HDCol1a1 mice carrying the collagenase transgene


IFNγinterferon gamma

IGFinsulin growth factor

IHCimmunohistochemical analysis


IL-17Ainterleukin 17A

MCP-1monocyte chemotactic protein 1 CCL2

MIP-1αmacrophage inflammatory protein 1 alpha CCL3

MMTVmouse mammary tumor virus

NSAIDnon-steroidal anti-inflammatory drug

OSEMordered-subset expectation maximization

PDGF-ββplatelet-derived growth factor ββ

PETpositron emission tomography

PGE2prostaglandin E2

PTGS2prostaglandin-endoperoxide synthase 2

PyMTpolyomavirus middle T

RANTESregulated on activation, normal T cell expressed and secreted CCL5

SCFstem cell factor

TACS-3tumor associated collagen signature-3

TAMstumor-associated macrophages

TANstumor-associated neutrophils

TNFαtumor necrosis factor alpha

VEGFvascular endothelial growth factor



αSMAalpha smooth muscle actin

β-NGFnerve growth factor β

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-016-0695-3 contains supplementary material, which is available to authorized users.

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Author: Karla Esbona - David Inman - Sandeep Saha - Justin Jeffery - Pepper Schedin - Lee Wilke - Patricia Keely


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