Breast carcinoma models for studying role of metastasis associated one (MTA1) gene in metastasis.

摘要

In the year 2005 cancer, for the first time, became the number one cause of death in the United States induced by disease, exceeding cardio-vascular diseases. Breast cancer is the second most common cause of death from cancer in women. More then 90% of these women die not from complications associated with a primary tumor, but rather from metastases. Understanding the complexity of the metastatic process and finding markers that would accurately predict the metastic capacity of primary tumor cells would potentially increase patients' survival.; Overexpression of m&barbelow;etastasis-a&barbelow;ssociated gene 1 (MTA1) has been previously linked to increased metastasic propensity of a variety of malignancies, including solid tumors and cancer cell lines. Clinical observation of better prognosis in a group of patients with non-metastatic breast tumors expressing LOH on chromosome 14qter, and later mapping of MTA1 to this region, reinforced MTA1's role in metastasis and made MTA1 one of the potential metastatic prognostic markers.; To further understand the function of MTA1 gene and its role in metastasis we overexpressed MTA1 in selected breast cancer cell lines (MCF-&, and MDA-MB-231), and looked at the global gene expression changes resulting from this overexpression. The Affymetrix HG-133A_2 microarray gene expression profiling analysis identified a statistically significant group of genes that play an important role in G2-S phase of cell cycle and in assembly of the mitotic apparatus. Some of these genes e.g., CDC25C, KI-67, STK6, and TOP2A have been previously identified as significant players in cancer biology.; To investigate involvement of MTA1 in metastasis in the context of a living organism, we generated an in vivo transgenic mouse model expressing MMTV promoter-driven MTA1 and EGFP transgenes in mammary gland tissue. After initial molecular analysis of MTA1 overexpression and its influence on normal mammary gland development, animals were crossed to three different mouse models of breast cancer overexpressing myc, neu, and ras oncogenes. Animal-to-animal variability of MTA1 transgene expression and absence of MTA1 overexpression in mammary gland derived tumors precluded us from our proposed exploration of MTA1 function. Analysis of MMTV promoter sequences did not show that DNA methylation was responsible for this expressional inconsistency and left us with a speculation that site of the transgene integration was most probably responsible for the expressional failure of the transgene.