ABSTRACT
Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3ß and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , PTEN Phosphohydrolase/metabolism , Prostatic Neoplasms/metabolism , Protein Phosphatase 2/metabolism , Animals , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Disease Progression , Enzyme Activation , G1 Phase Cell Cycle Checkpoints , Gene Knockdown Techniques , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Membrane Proteins , Mice , Mice, Nude , Mice, Transgenic , Neoplasm Transplantation , Phosphorylation , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/pathology , Protein Processing, Post-Translational , Protein Transport , Reactive Oxygen Species/metabolism , Signal Transduction , Tissue Array Analysis , Tumor BurdenABSTRACT
Prostate cancer (CaP) is the most common cancer among adult men in the Western world. Better insight into its tumor-activating pathways may facilitate the development of targeted therapies. In this study, we show that patients who develop prostate tumors with low levels of PTEN and high levels of HER2/3 have a poor prognosis. This is functionally relevant, as targeting Her2 activation to the murine prostate cooperates with Pten loss and drives CaP progression. Mechanistically, this is associated with activation of the MAPK pathway and abrogation of the Pten loss-induced cellular senescence program. Importantly, inhibition of MEK function strongly suppressed proliferation within these tumors by restoring the Pten loss-induced cellular senescence program. Taken together, these data suggest that stratification of CaP patients for HER2/3 and PTEN status could identify patients with aggressive CaP who may respond favorably to MEK inhibition.
Subject(s)
Cellular Senescence , Genes, erbB-2 , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/pathology , Animals , Humans , Immunohistochemistry , Male , Mice , Mice, Transgenic , Prognosis , Prostatic Neoplasms/geneticsABSTRACT
GRP78/BiP is a key member of the molecular chaperone heat shock protein (Hsp) 70 family. It has a critical role in prostate cancer (PC) including Pten loss-driven carcinogenesis, but the molecular basis of this remains unclear. We investigated the effect of GRP78 and its putative client proteins, including androgen receptor (AR) in clinical PC. Expression of GRP78 and key Hsp70-hsp90 client proteins (HER2, HER3, AR and AKT) were studied in an incidence tissue microarray (TMA) of prostate cancer. The relationship of GRP78 and AR was further tested in in vitro cell models (LNCaP and its derived LNCaP-CR subclone) and a matched TMA of hormone-naïve (HNPC) and castrate-resistant prostate cancer (CRPC). In vitro and in vivo expression of GRP78 and client proteins were assessed by western blotting and immunohistochemistry, respectively, using the weighted histoscore method. Significant co-expression of GRP78, pAKT, HER2, HER3 and AR was observed in PC. Abnormal AR, GRP78 and pAKT expression have significant impact on patient survival. GRP78 expression in AR(+) tumours was significantly higher than in AR(-) tumours. In keeping with our clinical data, activation of AR by dihydrotestosterone (DHT) potently activated GRP78 expression in both LNCaP and LNCaP-CR cells. For the first time, using a matched HNPC and CRPC TMA, enhanced cytoplasmic and membranous GRP78 expression was observed in CRPC. Future prospective studies are therefore warranted to validate GRP78 as prognostic marker and therapeutic target, in the context of the AR and pAKT status. In summary, GRP78 is co-expressed with Hsp70-hsp90 client proteins. Up-regulated expression of AR and GRP78 expression in untreated prostate cancer predicts a less favourable outcome. This points to the importance of understanding in the molecular interaction among AR, GRP78 and AKT.
Subject(s)
Heat-Shock Proteins/biosynthesis , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Up-Regulation , Biomarkers, Tumor/metabolism , Disease Progression , Endoplasmic Reticulum Chaperone BiP , Gene Expression Regulation, Neoplastic , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , Male , Neoplasm Proteins/metabolism , Orchiectomy , Prostatic Neoplasms/surgery , Survival Analysis , Tumor Cells, CulturedABSTRACT
AIMS: Keratinizing squamous metaplasia is infrequently found in bladder biopsies and its clinical significance remains unclear, with studies linking it to the development of invasive squamous cell carcinoma. Once diagnosed, there is a dilemma how to treat and follow-up this group. METHODS: We reviewed the literature on the topic with particular emphasis on natural history, management and subsequent follow-up. RESULTS: Keratinizing squamous metaplasia of the bladder is rare. Pathognomonic findings on biopsy are required to confirm the diagnosis. Both synchronous diagnosis of urothelial tumour and subsequent tumour development on follow-up has been identified. Risk of malignant transformation increases in the presence of dysplasia as well as with extensive keratinization. Lesions should be treated with local transurethral resection. Considering the lack of evidence cystectomy cannot be justified for those with extensive lesions. CONCLUSION: Currently there is not enough data to identify keratinizing squamous metaplasia of the bladder as a pre-malignant condition; this term being reserved for those with obvious histological dysplasia. However at present all patients should undergo regular follow-up.
Subject(s)
Carcinoma, Squamous Cell/pathology , Precancerous Conditions/pathology , Urinary Bladder Neoplasms/pathology , Urinary Bladder/pathology , Carcinoma, Squamous Cell/surgery , Disease Progression , Humans , Metaplasia , Precancerous Conditions/surgery , Treatment Outcome , Urinary Bladder Neoplasms/surgery , Urologic Surgical Procedures , Urothelium/pathologyABSTRACT
The role of immunohistochemical markers in distinguishing peritoneal mesothelioma from primary or metastatic serous papillary carcinoma of the peritoneum was evaluated. We immunostained 20 peritoneal mesotheliomas (from 14 men and 6 women), 14 primary peritoneal carcinomas, and 14 metastatic serous ovarian carcinomas with a panel of 16 antibodies. Positive staining for calretinin was identified in 17 (85%) of 20 mesotheliomas, but all carcinomas were negative. Positive staining for Ber-EP4 was identified in 27 (96%) of 28 carcinomas and in 2 (10%) of 20 mesotheliomas. Estrogen receptors were positive in 26 (93%) of 28 carcinomas, and progesterone receptors were positive in 8 (29%) of 28 carcinomas. All mesotheliomas were negative for estrogen and progesterone receptors. The other antibodies evaluated were insufficiently sensitive and/or specific to be diagnostically useful. In conjunction with calretinin and Ber-EP4, estrogen and progesterone receptors are useful discriminatory markers for distinguishing peritoneal mesothelioma from primary or metastatic serous carcinoma.
