New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

Abstract

The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer.

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model

“…The potential role of inflammation in driving high mammographic density suggests that use of non-steroidal anti-inflammatory drugs (NSAID), which are already known to reduce breast cancer risk [63, 64], could be effective in reducing mammographic density. In a mouse model of HMD, Celecoxib, a selective NSAID that specifically inhibits COX2, was shown to reduce collagen deposition in the mammary gland, and reduce tumour development and metastasis [65].…”

Interleukin-1β activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells

“…Obesity and post-partum involution are chronic inflammatory states in mammary glands, and are associated with increased breast cancer risk (3). Furthermore, non-steroidal anti-inflammatory drugs (NSAID), which are nonselective Prostaglandin G/H synthase 2, or cyclooxygenase-2 (COX-2) inhibitors, significantly reduce the risk of mammary carcinogenesis, recurrence, and motility of breast cancer (4).…”

Anesthetic drug propofol inhibits the expression of interleukin‑6, interleukin‑8 and cyclooxygenase‑2, a potential mechanism for propofol in suppressing tumor development and metastasis

“…The meta-analysis of 90 studies conducted by Harris (16) indicated that regular administration of selective COX-2 inhibitors significantly reduced the incidence of colon, breast, lung and prostatic cancer. As breast cancer has been studied more extensively in recent years, the effects of COX-2 have been increasingly highlighted (17,18). Animal experiments have demonstrated that the overexpression of COX-2 induced the genesis of breast cancer in transgenic mice (19).…”