Research Article: Pten Dose Dictates Cancer Progression in the Prostate

Date Published: December 27, 2003

Publisher: Public Library of Science

Author(s): Lloyd C Trotman, Masaru Niki, Zohar A Dotan, Jason A Koutcher, Antonio Di Cristofano, Andrew Xiao, Alan S Khoo, Pradip Roy-Burman, Norman M Greenberg, Terry Van Dyke, Carlos Cordon-Cardo, Pier Paolo Pandolfi

Abstract: Complete inactivation of the PTEN tumor suppressor gene is extremely
common in advanced cancer, including prostate cancer (CaP). However, one
PTEN allele is already lost in the vast majority of CaPs at presentation.
To determine the consequence of PTEN dose variations on cancer progression, we have
generated by homologous recombination a hypomorphic Pten mouse mutant
series with decreasing Pten activity: Ptenhy/+
> Pten+/− >
Ptenhy/− (mutants in which we have rescued the
embryonic lethality due to complete Pten inactivation) >
Pten prostate conditional knockout (Ptenpc)
mutants. In addition, we have generated and comparatively analyzed two distinct
Ptenpc mutants in which Pten is inactivated
focally or throughout the entire prostatic epithelium. We find that the extent of
Pten inactivation dictate in an exquisite dose-dependent fashion CaP
progression, its incidence, latency, and biology. The dose of Pten affects key downstream
targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive
genetic support for the notion that PTEN is haploinsufficient in tumor
suppression and that its dose is a key determinant in cancer progression.

Partial Text: The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor
suppressor gene is located on chromosome 10q23, a genomic region frequently lost in human
cancers. Somatic deletions or mutations of this gene have been identified in a large
fraction of tumors, frequently in prostate cancer (CaP), placing PTEN among
the most commonly mutated tumor suppressor genes in human cancer (Cantley and Neel 1999; Di Cristofano and Pandolfi 2000).

Our analysis allows a detailed deconstruction the molecular genetics underlying cancer
progression in the prostate and the assessment of the key relevance of Pten and subtle
variations in its dose in controlling this process. Based on our findings, we can now
attribute distinct preneoplastic or malignant pathological entities to distinct molecular
states. Furthermore, this new knowledge allows the reclassification, on the basis of their
true molecular nature, of pathological lesions that at a superficial analysis appeared very
similar (Figure 6).



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