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Introduction
A number of epidemiological and clinical studies have presented evidence that chronic inflammation caused by microbial infection, as well as chemical irritants, significantly increases cancer risk (1,2). 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). In the tumor microenvironment, various inflammatory cells, such as tumor-associated macrophages, are recruited to form a pro-tumor inflammatory environment. Inflammatory cells produce a variety of mediators, including growth factors, chemokines and cytokines, which induce tumor growth, invasion, and angiogenesis (5,6).
Proinflammatory cytokines are a major determinant for the invasiveness of tumor cells. Among these cytokines, interleukin-1β (IL-1β) is abundant in tumor tissues and stimulates tumor growth, invasion, carcinogenesis and host-tumor association (7). IL-1β-knockout mice are resistant to the development of chemically induced tumors (8), and exhibit suppressed tumor invasion and angiogenesis (9,10). On the other hand, stomach-specific IL-1β overexpression induces gastric inflammation and cancer (11). These results identify IL-1β as one of the essential components mediating inflammation-associated tumor progression. IL-1β stimulation of tumor cells activates multiple signaling pathways involving protein kinase B, mitogen activated protein (MAP) kinase, and nuclear factor-κB (12). Activation of these signaling molecules is required for IL-1β-mediated production of matrix metalloproteinase (MMP)-9, a matrix degrading enzyme that is regarded as a critical regulator in IL-1β-induced tumor invasion (13–15). A number of studies have investigated the association between MMP expression and the prognosis of breast cancer patients. Most recently, a meta-analysis by Ren et al (16) reported that MMP-9 overexpression in serum was associated with poor patient prognosis in breast cancer.
Proto-oncogene tyrosine-protein kinase Src (Src) is a non-receptor tyrosine kinase that is comprised of SH3, SH2, and kinase domains. Extracellular stimuli including cytokines, growth factors and integrin engagement, activate Src, which in turn, phosphorylates various target proteins to regulate cell proliferation, differentiation, and migration (17,18). Among these target proteins, focal adhesion kinase 1 (FAK) is essential for the regulation of signal transduction, cell adhesion and migration carried out by Src (19). FAK is composed of an N-terminal FERM domain, a central kinase domain, and...