2007-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/697258Metastasis is the most fearsome aspect of cancer. Most deaths from cancer are due to metastases that are resistant to conventional therapies. The main steps in the formation of a metastasis are as follows: (a) Cellular transformation and tumor growth. (b) Angiogenesis and lymphangiogenesis. (c) Enter the circulation by intravasation. (d) Transport and arrest in the target organ. (e) Invade to target organ by extravasation. (f) Proliferation within the organ parenchyma completes the metastatic process. During these processes, the tumorigenicity and migratory ability of a cancer cell are critical for tumor progression. Connective tissue growth factor (CTGF), one of the CCN gene family members, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth, apoptosis and differentiation. CTGF is overexpressed in various human cancers including breast cancer and its expression level is correlated with advanced stages of breast cancer patients. Also, it has been indicated that in breast cancer cells, CTGF play a critical role in osteolytic metastasis formation. However, the molecular mechanisms of how CTGF involve in breast cancer progression are still largely unknown. According to our preliminary data, we found that CTGF confers enhanced migratory ability through ERK1/2-dependent pathway in breast cancer cells. Moreover, preliminary animal experiments showed that CTGF is critical for tumorigenicity. By using cDNA microarray analysis, we found a series of genes that are regulated by CTGF, including S100A4, amphiregulin, and CSF-1, which are important for cell migration, growth, and signal transduction. Accumulating preliminary data provide strong evidences for us to further investigate the molecular mechanism in detail. This study is aimed to identify the role and the molecular mechanism of CTGF in breast cancer progression both in vitro and in vivo. Specifically, the major three goals are as follows: First, we will investigate the role of CTGF in breast cancer both in vitro and in vivo. Secondary, we will identify the receptors, downstream effectors, and signal transduction pathways that involved in the CTGF-regulated signaling cascades. Finally, we will focus on the investigation of clinical correlation between CTGF and its downstream effectors. More important, we will test the therapeutic potential of CTGF-neutralizing antibody by animal models. Eventually, we hope that through understanding of the mechanism can provide a novel strategy for the prevention and therapy in breast cancer patients.