Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Disorders in cell circuitry in cancer: Exploitable targets for prevention and therapy

IB Weinstein

Herbert Irving Comprehensive Cancer Center, New York, NY

The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control. Thus, cyclin D1 is frequently overexpressed in a variety of human cancers. Cyclin D1 plays a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes; and an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells. Therefore, inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitor protein p27Kip1 in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27Kip1. Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27Kip1 showed increased sensitivity to induction of differentiation. This may explain why decreased p27Kip1 in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27Kip1 may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apoptosis. On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from “gene addiction” and “gene hypersensitivity,” disorders that might be exploited in both cancer prevention and therapy. Recent findings on the roles of protein kinase G and the jun kinase pathway in apoptosis and cancer chemoprevention will also be described.

KEY WORDS: p27, cDNA, p27Kip1, chemoprevention.

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on molecular detection & therapy.