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PTEN and prostate cancer--the devil is in the doses


Cancer is a complex disease where multiple genetic and environmental factors contribute to risk. Its onset and progression depends on the combination of a series of genetic disruptions rather than on a single event. At a genetic level, it is not just presence or absence of a gene (or a mutated version of the gene) that causes disease, but as Pier Paolo Pandolfi and colleagues report, protein "dose"--that is, the level of remaining activity--also influences cancer progression.

Focusing on the tumor suppressor gene PTEN, the researchers created a mouse model system to study tumor progression in prostate cancer. PTEN is among the most commonly mutated tumor suppressor genes in human cancer. And like many other tumor suppressors, PTEN targets proteins in signaling pathways that regulate cell growth and apoptosis in healthy tissue and contributes to cancer when dysfunctional. Humans, as diploid organisms, generally have two versions of most genes, including PTEN. In the event that one copy is damaged or lost, gene function is usually maintained by the other copy. In the classic definition of a tumor suppressor, both copies must be lost for a tumor to occur. Yet in many cases of advanced cancer, including prostate cancer, only one copy is lost at the time a patient shows symptoms. It is then not unreasonable to hypothesize that the degree of remaining PTEN activity controls the course of the disease: loss of one copy could influence tumor initiation, while further slight reductions might be sufficient to facilitate the invasion and metastatic behavior of late-stage cancers.

Pandolfi and colleagues chose two strategies to investigate this hypothesis. In the first approach, they genetically engineered one series of mice with minimal levels of murine PTEN protein (complete loss results in embryo death). This novel 25%–35% active PTEN "hypomorphic" strain of mice, which appears to retain the minimum level of PTEN needed to survive embryonic development, adds to existing strains of fully normal and 50% active PTEN mice. In order to model the full loss of PTEN protein, the researchers generated another series of mice in which PTEN genes were selectively disabled in the prostate only. The researchers found that subtle reductions in PTEN dose did indeed produce progressive changes in the biology of the tumor, while mice having no functional PTEN genes showed the most invasive and aggressive cancers. These results, the researchers say, show that PTEN plays a "crucial dose-dependent role in prostate cancer tumor suppression" and that progressive reduction of gene function induces progressive changes in the quantity and quality of molecular and pathological effects on the pathway to full-blown cancer.

By coupling the molecular genetics and dose of PTEN protein with the physiological progression of cancer in the prostate, these new mouse models may not only shed light on cancer progression in humans, but also help bolster diagnostic, prognostic, and therapeutic techniques. While evaluation of tumor status has traditionally been determined by pathological analysis of tissue samples, these new models allow scientists to pair anatomical stages with underlying molecular events--such as the expression level of a single gene or protein--to allow more accurate assessments. These molecular profiles can also help researchers design targeted, more efficient prostate cancer treatments. For example, if prostate tissue is hypersensitive to PTEN in humans--which the results suggest may be the case, since male mice with only 30% of normal PTEN levels show massive and selective enlargement of the prostate, and even invasive tumors--then ongoing monitoring of PTEN levels could help tailor therapies based on promoting PTEN expression. For patients with complete loss of PTEN function, where this would not be an option, inhibiting the proteins made overactive through PTEN loss could prove effective. And these approaches could well hold true for other cancers involving PTEN, including endometrial, brain, and breast cancer.

Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, et al. (2003) PTEN dose dictates cancer progression in the prostate. DOI: 10.1371/journal.pbio.0000059

All works published in PLoS Biology are open access. Everything is immediately available without cost to anyone, anywhere -- to read, download, redistribute, include in databases, and otherwise use -- subject only to the condition that the original authorship is properly attributed. Copyright is retained by the author. The Public Library of Science uses the Creative Commons Attribution License.

This article, which appears in PDF form online on October 27, 2003, is presented as a pre-issue publication. The article will appear both as HTML (along with the PDF) and in print in our December 22, 2003 issue.

Dr. Pier Paolo Pandolfi
Molecular Biology Program and Department of Pathology
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, Box 110
New York, NY 10021
United States of America
212-717-3102 (fax)

Barbara Cohen | PLoS
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