Cyclin-Dependent P27 as a Prognostic Biomarker
The prognosis and clinical management of patients with cancer is commonly determined by traditional clinical and pathological factors. Nevertheless, patients may present with significantly different clinical outcomes despite similar clinicopathological features. This has prompted intense research to find biological markers that may closely reflect tumor biology and thereby clinical outcome. This article presents the current knowledge on the prognostic significance of p27 expression in cancer and its potential role as a target for future therapy.
The important role of certain cell cycle proteins in carcinogenesis and tumor progression is by now well established. Much effort has been invested in recent years in examining the impact of these proteins as potential biological markers for prognosis, as well as markers for response to therapy and targets for specific interventions. Traditional clinical and histological markers, which are commonly used today to assess prognosis and determine treatment protocols, are often inadequate and may lead to over- or under-treatment in a substantial number of cancer patients. Thus, the identification of novel biological molecular markers related to cancer progression may potentially improve the tailored application of adjuvant therapy for subgroups of high-risk patients and promote the discovery of novel targeted interventions.
As uncontrolled cellular proliferation is the main hallmark of cancer, alterations in the expression or activity of proteins which are intimately involved in cell cycle regulation are of particular interest as novel putative biological markers. Under normal circumstances, progression of the cell cycle is tightly controlled and is largely dependent on the timely activation and integration of cyclins and their respective cyclin-dependent kinases (Cdks). Cdks regulate checkpoints that integrate mitogenic and growth inhibitory signals, thereby coordinating cell cycle transitions. In turn, the activity of each Cdk is dependent on the presence of a particular cyclin. In addition, Cdks are negatively regulated by tight control of specific Cdk inhibitors (Cdki) at different phases of the cell cycle. Two families of Cdki regulate the different Cdks. Members of the Cdk4 (INK4) family, including p15, p16, p18 and p19, form complexes with Cdk4 and Cdk6 that prevent the binding of cyclin proteins. The CIP–KIP family includes p21, p27 and p57, which inhibit the kinase activity of the G1 Cdk2–cyclin A and Cdk2–cyclin E complexes and thus prevent G1–S phase transition. It has been recognized that some of these inhibitors have important roles in tumor suppression. There is strong evidence that among the different Cdki, deregulation of p27 plays a major role in tumor progression and the clinical outcome of many malignant diseases.
p27 is a 198-amino acid protein whose gene (CDKN1B) maps to the short arm of chromosome 12, and it was originally discovered in cells arrested by TGF-α. Studies have shown that p27 serves as an important regulator for both cellular proliferation and tissue differentiation. The essential role of p27 in the regulation of normal cell growth and differentiation is demonstrated by the finding of increased body size, organomegaly and spontaneous pituitary tumor formation in mice lacking p27, as well as by altered differentiation programs in p27-knockout cells.
Abstract and Introduction
Abstract
The prognosis and clinical management of patients with cancer is commonly determined by traditional clinical and pathological factors. Nevertheless, patients may present with significantly different clinical outcomes despite similar clinicopathological features. This has prompted intense research to find biological markers that may closely reflect tumor biology and thereby clinical outcome. This article presents the current knowledge on the prognostic significance of p27 expression in cancer and its potential role as a target for future therapy.
Introduction
The important role of certain cell cycle proteins in carcinogenesis and tumor progression is by now well established. Much effort has been invested in recent years in examining the impact of these proteins as potential biological markers for prognosis, as well as markers for response to therapy and targets for specific interventions. Traditional clinical and histological markers, which are commonly used today to assess prognosis and determine treatment protocols, are often inadequate and may lead to over- or under-treatment in a substantial number of cancer patients. Thus, the identification of novel biological molecular markers related to cancer progression may potentially improve the tailored application of adjuvant therapy for subgroups of high-risk patients and promote the discovery of novel targeted interventions.
As uncontrolled cellular proliferation is the main hallmark of cancer, alterations in the expression or activity of proteins which are intimately involved in cell cycle regulation are of particular interest as novel putative biological markers. Under normal circumstances, progression of the cell cycle is tightly controlled and is largely dependent on the timely activation and integration of cyclins and their respective cyclin-dependent kinases (Cdks). Cdks regulate checkpoints that integrate mitogenic and growth inhibitory signals, thereby coordinating cell cycle transitions. In turn, the activity of each Cdk is dependent on the presence of a particular cyclin. In addition, Cdks are negatively regulated by tight control of specific Cdk inhibitors (Cdki) at different phases of the cell cycle. Two families of Cdki regulate the different Cdks. Members of the Cdk4 (INK4) family, including p15, p16, p18 and p19, form complexes with Cdk4 and Cdk6 that prevent the binding of cyclin proteins. The CIP–KIP family includes p21, p27 and p57, which inhibit the kinase activity of the G1 Cdk2–cyclin A and Cdk2–cyclin E complexes and thus prevent G1–S phase transition. It has been recognized that some of these inhibitors have important roles in tumor suppression. There is strong evidence that among the different Cdki, deregulation of p27 plays a major role in tumor progression and the clinical outcome of many malignant diseases.
p27 is a 198-amino acid protein whose gene (CDKN1B) maps to the short arm of chromosome 12, and it was originally discovered in cells arrested by TGF-α. Studies have shown that p27 serves as an important regulator for both cellular proliferation and tissue differentiation. The essential role of p27 in the regulation of normal cell growth and differentiation is demonstrated by the finding of increased body size, organomegaly and spontaneous pituitary tumor formation in mice lacking p27, as well as by altered differentiation programs in p27-knockout cells.