COX-2 modulates mammary tumor progression in response to collagen density

Abstract

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/Col1a1tm1jae, 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/Col1a1tm1jae 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/Col1a1tm1jae 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0695-3) contains supplementary material, which is available to authorized users.

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

“…More recently in the Col1a1 tm1jae mouse model of high breast density, where a mutation in the collagen I collagenase cleavage site leads to increased collagen accumulation and subsequent mammary tumor promotion, celecoxib was found to suppress both phenotypes (55). Here, possibly for the first time, we identify a potential mechanism by which NSAIDs inhibit collagen deposition by demonstrating that the COX2 metabolite PGE2 induces, and ibuprofen suppresses, Col1a1, Mmp3, and Cxcl12 production in normal mammary fibroblasts.…”

“…In rodent models, systemic NSAID treatment after weaning inhibits fibrillar collagen accumulation in the involuting mammary gland through an unknown mechanism (5,55). To determine if systemic NSAID treatment inhibits collagen gene expression in mammary fibroblasts, we treated mice with control diet or ibuprofen at 2 different doses (equivalent to 117 mg and 234 mg per day for humans) (56), starting at weaning through InvD6 (Figure 2A).…”

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model

“…In a mouse model of HMD, Celecoxib, a selective NSAID that specifically inhibits COX2, was shown to reduce collagen deposition in the mammary gland, and reduce tumour development and metastasis [65]. Although there appears to be no association between NSAID use and mammographic density [66], a study of nearly 30,000 postmenopasual women found that NSAID use reduced the risk of increasing mammographic density over a period of 9–28 months [67].…”

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

“…Additionally, it is important to avoid use of commonly employed pain management drugs including non-steroidal anti-inflammatory drugs (NSAIDs) during or following the surgical procedure. NSAIDs have anti-tumor activity in certain breast cancers [62][63][64][65] , and some classes of NSAIDs increase the risk of hepatotoxicity 66,67 , potentially compromising the study of liver metastasis and the liver metastatic niche. Further, studies suggest that NSAIDs directly influence the tissue microenvironment, reducing pro-metastatic extracellular matrix proteins tenascin-C 68 and fibrillar collagen 62,65 .…”

“…NSAIDs have anti-tumor activity in certain breast cancers [62][63][64][65] , and some classes of NSAIDs increase the risk of hepatotoxicity 66,67 , potentially compromising the study of liver metastasis and the liver metastatic niche. Further, studies suggest that NSAIDs directly influence the tissue microenvironment, reducing pro-metastatic extracellular matrix proteins tenascin-C 68 and fibrillar collagen 62,65 . Alternatively, the use of an opioid derivative, buprenorphine, was used because of its efficacy in rodent pain management 69 and due to the lack of evidence that opioids have anti-tumor activity 70 .…”