Abstract P1-06-02: Inflammatory stromal cell response induced by collagen dense stroma is regulated by cyclooxygenase-2 in a mouse breast cancer model
Authors: Esbona K , Inman D , Eliceiri K , Wilke LG , Keely PJ 
Published: August 2014

Abstract
Breast cancer is the most common invasive cancer in women, causing 40,000 deaths yearly in the United States. Increased mammographic density correlates with over four-fold increase risk for breast cancer, making it one of the greatest risk factors known for this disease. High breast density is mainly attributable to elevated collagen matrix deposition in the breast tissue, and we have found that increased collagen in the Col1a1tm1jae mouse model promotes mammary tumor formation and progression. Increased collagen density in vitro increases expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2), by over four fold. COX-2 over-expression is observed in 40% of invasive breast carcinoma cases and correlates with poor prognosis. Based on these findings, we hypothesized that inhibition of COX-2 may be an effective therapeutic in the context of mammary tumors arising in dense tissue. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID) that specifically inhibits COX-2. To understand how COX-2 affects response to collagen matrix density, we utilized our previously characterized mouse model of MMTV-PyVT tumors in a wild type (wt) or Col1a1tm1jae background (HD, High Density). Col1a1tm1jae heterozygote or wt littermates were randomly assigned at 11 weeks of age to treatment with vehicle or celecoxib at 0.2mg per mouse per day. Oral treatment was given daily for 21 days. We found that MMTV-PyVT tumors responded to celecoxib in a manner that is regulated by matrix density. Tumors that arose on the dense Col1a1tm1jae background (HD) were larger and more invasive (p &lt; .0001) and expressed higher levels of COX-2 and PGE2 than their wt littermates. Both COX-2 (wt: p = 0.0025, HD: p &lt; 0.0001) and PGE2 (wt: p = 0.0196, HD: p = 0.0002) levels were decreased in animals treated with celecoxib. However, Ki-67 and syndecan 1 levels decreased only in HD mice that received treatment with celecoxib (p = 0.0003, p = 0.0007, respectively). In addition, total number of macrophages (wt: p = 0.0052, HD: p &lt; 0.0001) and fibroblasts (wt: p = 0.0133, HD: p = 0.0003) were diminished in animals treated with celecoxib independently of collagen density. On the other hand, cancer associated fibroblast (CAF) population was diminished only in HD mice treated with celecoxib (p = 0.0002) which, along with the synedan-1 result suggests that celecoxib selectively abrogates the inflammatory response from reactive stroma only. Consequently, we find that celecoxib treatment remodels collagen fiber organization, such that it more closely resembles wt assembly. Ongoing studies will identify different macrophage populations, and which stromal cell populations express COX-2 and PGE2. These findings suggest that COX-2 has a direct role in modulating tumor progression in dense matrices which promote invasion. Moreover, these findings suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-02.