Genomic Rearrangements of PTEN in Prostate Cancer

Abstract

The phosphatase and tensin homolog gene (PTEN) on chromosome 10q23.3 is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen-independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy

“…Although we used cultured PCa cell lines and xenografts as model systems, we note that MYC and DAXX mRNA levels are similarly increased in human prostate cancers and are associated with poor prognosis (8,47) (Fig. 9), whereas PTEN levels are decreased (51). Furthermore, therapyinduced autophagy enhances tumor cell death in a context-dependent manner (46), consistent with a tumor suppressor role for autophagy.…”

“…Compelling data show that the PTEN tumor suppressor, which is deleted in 40% of localized PCa and mutated in 60% of metastases (51), has a vital role in human PCa (52). PTEN loss may account for increased AKT activation and decreased autophagy in PCa, because introducing PTEN in cancer cells that lack PTEN function negatively regulates AKT (50).…”

PTEN and ERG Molecular Networks in Prostate Cancer

“…Various growth factors (epidermal growth factor EGF, platelet-derived growth factor receptor PDGF, insulin-like growth factor (IGF) may initiate the PIP3-Akt pathway by activating receptors of tyrosine kinases leading to the phosphoryliation of PI3K at the level of the cell membrane. The phosphorylated PI3K triggers the conversion of PIP2 to PIP3 and mediates the phosphorylation of Akt through PDK1 [5]. Activated Akt has a profound role in carcinogenesis by promoting cell growth and protein synthesis by regulating the mammalian target of rapamycin (mTOR) pathway.…”

“…Activated Akt has a profound role in carcinogenesis by promoting cell growth and protein synthesis by regulating the mammalian target of rapamycin (mTOR) pathway. Moreover, apart from interaction with the mTOR pathway Akt may also directly interact with the androgen receptor in an androgen independent manner leading to androgen receptor overactivation resulting to the development of castration resistant prostate cancer [5,6]. IGF signaling cascade is already known to be involved in prostate carcinogenesis.…”

“…The protein product is a dual lipid phosphatase acting as a negative regulator of the PIK3/Akt survival pathway by negatively regulating the intracellular levels of PIP3 by removing the 3-phosphatase from PIP3 converting it back to PIP2. As a result, the phosphorylation of Akt mediated by PIP2 conversion to PIP3 is inhibited and a G1 cell cycle arrest is induced [5,8]. Apart from interacting with the PIP3-Akt pathway, PTEN also presents PIP3 independent mechanisms of genomic stability regulation with involvement also in the MAPK signaling pathway [9].…”