The role of COX-2 and COX-derived prostaglandins in breast cancer cell-induced ADAMTS1 expression in fibroblasts
Chao-Kai Hsu (許朝凱)1, Shiaw-Wei Tyan (田孝威)1,2∗
1Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan, R.O.C. (嘉南藥理大學 生物科技系)
2Drug Discovery and Development Center, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan, R.O.C. (嘉南藥理大學 新藥創建研究中心)
Our previous study showed that breast cancer-associated fibroblasts (CAFs)
expressed high level of ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1) to increase invasion of cancer cells. Through co-culturing with breast cancer cells for at least four passages, breast normal tissue-associated fibroblasts (NAFs) obtained persistent activity for promoting cancer cell invasion via enhancing ADAMTS1 expression to the identical level of CAFs. ADAMTS1 has been shown to be up-regulated by cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2), so we tested the hypothesis that breast cancer cells might induce ADAMTS1 expression in NAFs via a COX/prostaglandin signaling pathway.
By using a COX-2 inhibitor NS398, we found that inhibition of COX-2 activity completely repressed the enhanced ADAMTS1 expression in NAFs that were
co-cultured with breast cancer MDA-MB-468 cells. Inhibition of COX-2 activity also reduced the ability of breast cancer cell-cocultured NAFs to promote cancer cell invasion. AH6809, an antagonist for EP1 and EP2 receptors (PGE2 receptors), and AL8810, an antagonist for a FP receptor (a PGF2 receptor), both exhibited ~70% of repression on the enhanced ADAMTS1 expression in breast cancer cell-cocultured NAFs. The results indicated that other COX-downstream signaling pathways might also induce ADAMTS1 expression. Furthermore, the treatment of a COX-2 inhibitor did not decrease the ADAMTS1 mRNA level in CAFs, which might be due to
irreversible change of fibroblasts once induced by cancer cells. Our results suggested that breast cancer cells may induced ADAMTS1 expression in stromal fibroblasts via a COX/prostaglandin signaling pathway to facilitate cancer cell invasion. The
COX/prostaglandin pathway in stromal cells may be a target for prevention of breast cancer progression.
Key words: breast cancer cell, fibroblast, COX-2, prostaglandin, ADAMTS1
