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.
Barbara Cohen | PLoS
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