Increased cyclooxygenase-2 (cox-2) expression and activity in a murine model of metastatic breast cancer

Abstract

Elevated prostaglandin E 2 (PGE 2 ) production is a common feature of human malignancies. This activity has often been attributed to increased metabolic activity of the cyclooxygenase enzymes, although a direct comparison of these 2 parameters i.e., prostaglandin production and cox protein expression, is rarely performed in the same malignant tissue. Using a murine model of metastatic breast cancer, we show that PGE 2 levels are positively correlated with increased tumorigenic and metastatic potential. Because prostaglandin synthesis is a product of 2 isoforms of the cyclooxygenase enzyme, we examined the expression and activity of both isoforms. All tumor cell lines examined, regardless of phenotype, express both cox-1 and cox-2 proteins in vitro. In contrast to the uniform cox-2 expression in vitro, only tumors resulting from the transplantation of metastatic cell lines express cox-2 in vivo. Cox-1 is detected in both metastatic and nonmetastatic tumors. Thus, this is the first evidence that, in the tumor milieu, cox-2 expression can be regulated differently in metastatic vs. nonmetastatic lesions. Examination of PGE 2 synthesis in vitro reveals that nearly complete inhibition of prostaglandin synthesis occurs in the presence of either indomethacin, which inhibits both isoforms, or NS398, which is selective for the cox-2 isoform. Thus, even though cell lines express both isoforms, the majority of the prostaglandin synthesis stems from the activity of the inducible, cox-2 isoform. Likewise, cell growth is inhibited by both indomethacin and NS398 in a dose-dependent manner, albeit at higher drug concentrations than required to ablate PGE 2 synthesis. Despite the inhibition of prostaglandin synthesis, the cox-2 enzyme levels (protein and mRNA) were increased by either indomethacin or NS398. © 2001 Wiley-Liss, Inc. Key words: cyclooxygenase; prostaglandin; breast cancer; metastasisHigh cyclooxygenase activity is a common feature of human epithelial malignancies, 1,2 however, the biological significance of this metabolic activity has never been established. Recent epidemiologic studies have indicated that prolonged use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a decreased risk of several malignancies, most notably colorectal cancers. 3 More recently, similar relationships have been observed in lung, breast and other cancers as well. 4 -6 Because NSAIDs have, as a principle action, inhibition of cyclooxygenases, these findings suggest that prostaglandin synthesis contributes to the risk of developing primary malignancies.We sought evidence for a role of prostaglandin synthesis in late tumor progression, i.e., tumor metastasis. Using a murine model of human breast cancer, we showed that higher prostaglandin E 2 (PGE 2 ) levels were observed in malignant mammary tissue in comparison to normal or premalignant gland. Furthermore, the highest PGE 2 levels were observed in the most malignant and metastatic tumors. 7 Two isoforms of cyclooxygenase (cox) are responsible for prostaglandin synthesis....

Role of β-arrestin 1 in the metastatic progression of colorectal cancer

“…These cells then travel to distant sites, extravasate from the vasculature, and reestablish growth. The expression of cyclooxygenase 2 has been associated with increased metastasis of breast, lung, and colon primary tumors (15)(16)(17), and cyclooxygenase-derived PGs such as PGE 2 and thromboxane A2 have been shown to directly stimulate cell migration (18,19). PGE 2 can induce the in vitro migration of WT LS-174T cells (4,18) as well as LS-174T cells overexpressing WT ␤-arrestin 1 (B-18) (Fig.…”

Bone resorption activity of osteolytic metastatic lung and breast cancers

“…Metastatic bone lesions can be osteoblastic, osteolytic, or mixed type. Previous studies usually grouped patients according to histological diagnosis [8,10,13,17,18,29,30,34,35]. In clinical setting; tumors with same histology (breast cancer, for instance) may demonstrate different (sclerotic, mixed, or lytic) types of bone metastasis.…”

“…Although metastatic tumor cells have the in vitro capability to destroy bone directly [ 101, the main mechanism of cancer-induced osteolysis consists of stimulation of osteoclast-mediated bone destruction [3,9,12,20,22,24,35]. PGE2 is an important local factor, and was reported to involve in cancerinduced bone destruction [3,12,13,17,22,25,26]. Ono et al [26] demonstrated that invasive breast cancers constitutively expressed inducible COX-2, enhanced osteoclast formation through the production of high levels of PGE2, and subsequently increased osteolysis.…”

COX-2 inhibits anoikis by activation of the PI-3K/Akt pathway in human bladder cancer cells

“…The levels of COX-2 expression are not only higher in cancer tissues than in normal tissues, but also strongly correlate with local invasion and metastasis (Kundu et al, 2001;Ohno et al, 2001;Yoshimura et al, 2001). Moreover, COX-2 selective inhibitors have been reported to inhibit tumor development in colons, breasts or urinary bladders (Grubbs et al, 2000;Steinbach et al, 2000;Orengo et al, 2002).…”