Abstract 1116: Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma

Abstract

Abstract 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 correlated to increased collagen 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 elevates expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2), by over four fold. Because COX-2 over-expression is observed in 40% of invasive breast carcinoma cases and correlates with poor prognosis, 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 made use of our previously characterized mouse model of MMTV-PyVT tumors in a wild type (wt) or Col1a1tm1jae background (HD). Col1a1tm1jae /+ or wild-type (+/+) 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 a link between matrix density and the role of COX-2. Tumors that arose on the dense Col1a1tm1jae background (HD) were larger and more invasive (p < .0001) and expressed higher levels of COX-2 and PGE2. COX-2 (wt = p = 0.0025, HD = p < 0.0001) and PGE2 (wt = p < 0.0196, HD = p = 0.0002) levels were both decreased in animals treated with celecoxib. Notably, cell proliferation as determined by Ki-67 staining decreased only in HD mice, and not in wt littermates, that received treatment with celecoxib (p = 0.0003, p = 0.0007, respectively). Additionally, the cancer associated fibroblast (CAF) population was diminished by celecoxib only in HD mice and not wt littermates (p = 0.0002). Celecoxib treatment altered collagen structure and the expression of the stromal protein, syndecan, only in Col1a1tm1jae/+ animals. Other features were affected by celecoxib in a non-density manner, as the total number of macrophages (wt = p = 0.0052, HD = p < 0.0001) and normal fibroblasts (wt = p = 0.0133, HD = p = 0.0003) were diminished in animals treated with celecoxib in both Col1a1tm1jae /+ and +/+ animals. Ongoing studies are aimed at identifying different macrophage populations, and which stromal cell populations are expressing COX-2 and PGE2. These findings suggest that COX-2 has a direct role in modulating tumor progression in dense matrices, which in turn promote more aggressive tumors. As dense breast tissue is a common occurrence, these findings suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue. Citation Format: Karla Esbona, David Inman, Sandeep Saha, Kevin Eliceiri, Lee G. Wilke, Patricia J. Keely. Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2014-1116