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Deregulated expression of p27(Kip1) in human breast cancers
A Sgambato1, Y J Zhang, N Arber
1Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Abstract:
Protein complexes composed of cyclins and cyclin-dependent kinases control the orderly progression of mammalian cells through the cell cycle. The p27(Kip1) protein belongs to a family of cyclin-dependent kinase-inhibitory proteins that are negative regulators of cell cycle progression and have been proposed as candidate tumor suppressor genes. However, the p27(Kip1) gene is only rarely mutated in human primary breast carcinomas and breast cancer cell lines. To further address the role of p27(Kip1) in the development of human tumors, we determined by Western blot analysis the levels of expression of the p27(Kip1) protein in a series of human cancer cell lines and found that this protein is expressed at high levels in many of these cell lines, even during exponential growth. The levels of p27(Kip1) were significantly associated with the levels of cyclins D1 and E. In contrast to the high level of p27(Kip1) in breast cancer cell lines, three cell lines established from normal mammary epithelium expressed low levels of this protein. Cell synchronization studies demonstrated deregulation of the expression of p27(Kip1) throughout the cell cycle in two breast cancer cell lines but normal regulation in a normal mammary epithelial cell line. Immunohistochemical studies on p27(Kip1) expression in 52 primary human breast cancers indicated that this protein was also expressed at relatively high levels in 44% of the tumor samples, but it was barely detectable or undetectable in the remaining 56% of the samples. Additional studies are required to determine why some breast cancer cells express relatively high levels of p27(Kip1) despite its known role as an inhibitor of cell cycle progression.
Insights
The p27 Kip1 protein, a cell cycle inhibitor, is highly expressed in many human cancer cell lines and breast tumors, despite its tumor suppressor role. Its expression is deregulated in some cancers, suggesting complex involvement in tumor development.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cyclin-dependent kinases (CDKs) and cyclins regulate cell cycle progression.
- p27 Kip1 is a CDK inhibitor proposed as a tumor suppressor gene.
- Rare mutations in p27 Kip1 contrast with its potential tumor suppressor role.
Purpose of the Study:
- Investigate the role of p27 Kip1 in human tumor development.
- Determine p27 Kip1 protein expression levels in cancer cell lines and primary tumors.
- Assess the regulation of p27 Kip1 during the cell cycle in cancer versus normal cells.
Main Methods:
- Western blot analysis of p27 Kip1 protein expression in cancer cell lines.
- Cell synchronization studies to examine cell cycle regulation.
- Immunohistochemical analysis of p27 Kip1 in primary human breast cancers.
Main Results:
- High p27 Kip1 expression observed in many cancer cell lines, even during active growth.
- p27 Kip1 levels significantly correlated with cyclin D1 and E levels.
- Normal mammary epithelial cells showed low p27 Kip1 levels, unlike cancer cells.
- Deregulation of p27 Kip1 expression observed in two breast cancer cell lines.
- 44% of primary breast cancers showed high p27 Kip1 expression; 56% showed low/undetectable levels.
Conclusions:
- p27 Kip1 is frequently overexpressed in human cancers, despite its inhibitory function.
- Deregulation of p27 Kip1 expression occurs in some breast cancers.
- The high expression of p27 Kip1 in tumors warrants further investigation into its role in cancer development.