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Heterochromatin Protein 1: Development of a Novel Breast Cancer Metastasis Marker
There is estimated to be 211,300 American women diagnosed with invasive breast cancer in 2003. The five-year survival rate for women with localized breast cancer is 97%, while the five-year survival rate for women with metastatic breast cancer is 23%. Metastasis is a serious problem in breast cancer, both for determining the individuals at risk and for treatment. We have determined that the chromosomal protein, HP1HSa, is down-regulated in metastatic breast tissue compared to primary tumors. Similarly, HP1HSa is down-regulated in highly invasive/metastatic breast cancer cell lines compared to poorly invasive/non-metastatic breast cancer cell lines. A reduction in in vitro invasion of highly invasive/metastatic breast cancer cells (that normally have low levels of HP1HSa) was observed upon expression of HP1HSa from a stable transgene, implying a critical role for HP1HSa in invasion. Deciphering the role of HP1HSa in breast cancer metastasis will lead to new diagnostic tests and/or treatments for metastasis. The heterochromatin protein 1 (HP1) family represents non-histone chromosomal proteins involved in chromosome segregation and gene expression. We propose that a reduction in expression of HP1HSa alters the metastatic potential of breast cancer cells through changes in gene expression. To identify the genes affected by a reduction in expression of HP1HSa, we propose to knock-down expression of HP1HSa. In Specific Aim 1, we will demonstrate knock-down of HP1HSa using RNAi based systems. In Specific Aim 2, we will determine if knock-down of HP1HSa in a poorly invasive cell line, MCF-7, results in increased invasion in an in vitro invasion assay system. In Specific Aim 3, we will determine the genes that change expression upon reduction of HP1HSa using Northern blot analysis for candidate genes and microarray analysis for global changes in gene expression. These experiments will reveal the molecular and physiological changes that occur upon down-regulation of HP1HSa. HP1HSa has the potential to be a diagnostic tool for identifying patients at risk for breast cancer metastasis and may be used for therapy. Understanding the mechanism by which HP1HSa prevents metastasis will aid in our general understanding of metastatic progression.
Metastasis, the process by which cells break away from a tumor and move throughout the body, is a serious problem for both the diagnosis and treatment of breast cancer. Although the five-year survival rate for women with a primary tumor is 97%, the five-year survival rate for women whose cancer has metastasized is 23%. Discovering molecular markers for metastasis is the first step towards better diagnosis, treatment, and therapy. We have shown that a chromosome-associated protein involved in gene regulation, HP1HSa, is present in reduced levels in metastatic breast cancer cells compared to non-metastatic breast cancer cells. To determine the role of HP1HSa in metastasis, we propose to reduce the amount of HP1HSa in non-metastatic breast cancer cells and examine the effects on invasion and gene expression. These studies will help to identify new diagnostic tests for patients with potentially metastatic tumors and new treatments for breast cancer metastasis.