Association With Cell Cycle

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Regarding cell growth, the cell cycle represents the most important biological process controlling cell proliferation. Many oncogenes and suppressor genes encode proteins operating throughout the cell cycle, leading eventually to uncontrolled cell growth. For example, some cyclins behave like oncoproteins whereas certain cell cycle inhibitors behave as proteins encoded by tumor suppressor genes. Products of the tumor suppressor gene may suppress cell growth by interacting with the cyclins and negatively regulating progression through the cell cycle. Mutations in the cyclin gene have been found in a variety of cancers.

8.1. Cyclin D1

Cyclin D1 is a protooncogene that plays a critical role in G1 progression of the cell cycle. Overexpression of the cyclin D1 locus was found in many human cancers as a result of gene amplification or translocations (65). Cyclin D1 is also the most frequently overexpressed in tumor. Because there is evidence that cell cycle derangement becomes worse as tumors progress to a more malignant state, the detection or measurement of cell cycle proteins has been used to determine a patient's prognosis. Amplification of Cyclin D1 gene has been observed in carcinomas of the breast, and head and neck, and translocated in parathyroid adenomas and centrocytic lymphomas (65). More than one-third of human breast cancers may contain excessive levels of cyclin D1, which accumulate through the deregulated expression of cyclin D1 without an apparent increase in gene copy number, indicating the prognostic significance of cyclin D1 protein.

Overexpression of cyclin D1 also occurs in most invasive ductal cancers of the breast, which can distinguish invasive breast caners from nonmalignant lesions. Abnormal coexpression of cyclin D1 and p53 protein contributes to the development of endometrial carcinoma (66).

Cyclin E is another G1 cyclin which can be severely expressed in many tumor cells. Altered expression of cyclin E protein (as oncogene) occurs in most of the breast tumor and increases with increase of grade and stage of the tumor. Alteration of cyclin E was also observed in other types of solid tumors as well as leukemia. It appears that cyclin Eprotein (not cyclin D protein) is the most consistent marker for determining the prognosis of early-stage node-negative ductal carcinomas. In breast cancer, the alteration in cyclin E expression becomes progressively worse with increasing stage and grade of the tumor, suggesting its potential as a new prognostic marker. Cyclin E alteration is reported as a more consistent event then c-erb B2 overexpression in breast cancer (67). Cyclin E protein overexpression was also found associated with p53 alteration and it was suggested that a simultaneous overexpression of both cyclin E and p53 is related to poor prognosis (66,68). According to Gong et al. (69) the expression of cyclin Eusually peaked at the time of cell entrance to S phase. Cyclin E will accumulate up to certain critical level before the initiation of DNA replication.

8.3. Cyclin-Dependent Kinase Inhibitor

The cell cycle is regulated by cyclin-dependent kinases (CDKs). Complexes of CDKs and their partner cyclins drive the cell through the cell cycle. Each complex phosphorylates a distinct set of proteins at a particular check-point or phase of the cycle. In addition, there are inhibitors for CDKs. Normal control of cellular growth requires a balance between the activators (cyclins) and the inhibitors of the CDKs. Several inhibitors of CDK can also be used as tumor markers. The several most common inhibitors of CDKs are listed below.

Mutation of p16 has been reported in several malignancies. Alteration in the p16 gene and its mutant protein have been found in several tumor cell lines and tumors, which include squamous cell carcinoma of the head and neck, esophageal squamous cell carcinoma, NSCLC, familial melanoma kindreds, primary bladder carcinoma, acute adult T-cell leukemia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia (70).

Although mutation in p27 is rare, reduced expression of p27 correlates with poor survival in cohorts of breast and colorectal carcinoma patients have been reported (71). High cyclin E and low p27 expression is associated with about 20% survival among all women tested and approx 30% survival in the node-negative subgroup.

Other cyclin dependent kinase inhibitors involving in malignancies include p21 in NSCLC and pancreatic adenocarcinoma, and p15 in leukemia, melanoma and metastatic lung cancer, and p57 in sarcomas and Wilms' tumors. Additional studies are needed in the future will verify their clinical utilities as tumor markers.

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