title: COX-2 modulates mammary tumor progression in response to collagen density.
abstract: BACKGROUND
  High 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 (tm1jae) , 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).
  
  
  METHODS
  To understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT/Col1a1 (tm1jae) 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.
  
  
  RESULTS
  PyMT/Col1a1 (tm1jae) 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA.|Institute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison, Madison, WI, USA.|School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Esbona
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA.|School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Inman
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.|School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saha
authors.affiliation: School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Jeffery
authors.affiliation: Department of Cell and Developmental Biology, School of Medicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Pepper
authors.initials: P
authors.lastname: Schedin
authors.affiliation: School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Wilke
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA. pjkeely@wisc.edu.|School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. pjkeely@wisc.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Keely
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000068579:Celecoxib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone