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A constitutively activated form of the p110 beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice

ABSTRACT: The global gene expression profiles of ventral prostates of wild type mice and p110 beta transgenic mice. normal prostate vs. prostate cancer induced by the overexpression of the active allele of p110 beta

ORGANISM(S): Mus musculus

SUBMITTER: S Lee

PROVIDER: E-GEOD-21543 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice.

Lee Sang Hyun SH Poulogiannis George G Pyne Saumyadipta S Jia Shidong S Zou Lihua L Signoretti Sabina S Loda Massimo M Cantley Lewis Clayton LC Roberts Thomas M TM

Proceedings of the National Academy of Sciences of the United States of America 20100601 24

Recent work has shown that ablation of p110beta, but not p110alpha, markedly impairs tumorigenesis driven by loss of phosphatase and tensin homolog (PTEN) in the mouse prostate. Other laboratories have reported complementary data in human prostate tumor lines, suggesting that p110beta activation is necessary for tumorigenesis driven by PTEN loss. Given the multiple functions of PTEN, we wondered if p110beta activation also is sufficient for tumorigenesis. Here, we report that transgenic expressi ...[more]

PMID: 20534477

Similar Datasets

A constitutively activated form of the p110 beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice

Project description:The global gene expression profiles of ventral prostates of wild type mice and p110 beta transgenic mice.

2010-05-20 | GSE21543 | GEO

A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice.

Project description:Recent work has shown that ablation of p110beta, but not p110alpha, markedly impairs tumorigenesis driven by loss of phosphatase and tensin homolog (PTEN) in the mouse prostate. Other laboratories have reported complementary data in human prostate tumor lines, suggesting that p110beta activation is necessary for tumorigenesis driven by PTEN loss. Given the multiple functions of PTEN, we wondered if p110beta activation also is sufficient for tumorigenesis. Here, we report that transgenic expression of a constitutively activated p110beta allele in the prostate drives prostate intraepithelial neoplasia formation. The resulting lesions are similar to, but are clearly distinct from, the ones arising from PTEN loss or Akt activation. Array analyses of transcription in multiple murine prostate tumor models featuring PI3K/AKT pathway activation allowed construction of a pathway signature that may be useful in predicting the prognosis of human prostate tumors.

| S-EPMC2890726 | biostudies-literature

Disruption of PPARg signaling results in mouse prostatic intraepithelial neoplasia (mPIN) involving active autophagy

Project description:Peroxisome proliferator-activated receptor-gamma (PPARg) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Following conditional prostatic epithelial knockout of PPARg in mice we observed focal hyperplasia of the epithelium which developed to mouse prostatic intraepithelial neoplasia (mPIN), becoming progressively more severe with time. We selectively knocked down PPARg2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically the results resembled the conditional PPARg KO mouse prostates. Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in both of PPARg- and g2- deficient cells. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. We conclude that PPARg maintains the maturation and turnover of peroxisomes and lysosomes in prostate epithelium. Disruption of PPARg signaling results in autophagy and oxidative stress during mPIN pathogenesis.

2009-12-07 | GSE13867 | GEO

Disruption of PPARg signaling results in mouse prostatic intraepithelial neoplasia (mPIN) involving active autophagy

2010-05-18 | E-GEOD-13867 | biostudies-arrayexpress

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.

2022-06-07 | GSE186419 | GEO

SENP1 induces prostatic intraepithelial neoplasia through multiple mechanisms.

Project description:SUMOylation has been shown to modulate DNA replication/repair, cell cycle progression, signal transduction, and the hypoxic response. SUMO (small ubiquitin-like modifier)-specific proteases regulate SUMOylation, but how changes in the expression of these proteases contribute to physiological and/or pathophysiological events remains undefined. Here, we show that SENP1 (sentrin/SUMO-specific protease 1) is highly expressed in human prostate cancer specimens and correlates with hypoxia-inducing factor 1alpha (HIF1alpha) expression. Mechanistic studies in a mouse model indicate that androgen-driven expression of murine SENP1 leads to HIF1alpha stabilization, enhanced vascular endothelial growth factor production, and angiogenesis. Further pathological assessment of the mouse indicates that SENP1 overexpression induces transformation of the normal prostate gland and gradually facilitates the onset of high-grade prostatic intraepithelial neoplasia. Consistent with cell culture studies, SENP1 enhances prostate epithelial cell proliferation via modulating the androgen receptor and cyclin D(1). These results demonstrate that deSUMOylation plays a critical role in prostate pathogenesis through induction of HIF1alpha-dependent angiogenesis and enhanced cell proliferation.

| S-EPMC2919148 | biostudies-literature

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.

2022-06-07 | GSE189784 | GEO

Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice.

Project description:ELL-associated factor 1 is a transcription elongation factor that shares significant homology and functional similarity to the androgen-responsive prostate tumor suppressor ELL-associated factor 2. EAF2 is frequently down-regulated in advanced prostate cancer and Eaf2 deletion in the mouse induced the development of murine prostatic intraepithelial neoplasia. Here we show that similar to EAF2, EAF1 is frequently down-regulated in advanced prostate cancer. Co-downregulation of EAF1 and EAF2 occurred in 40% of clinical specimens with Gleason score >7. We developed and characterized a murine model of prostate-epithelial specific deletion of Eaf1 in the prostate and crossed it with our previously generated mouse with conventional deletion of Eaf2. The prostates of Eaf1 deletion mice displayed murine prostatic intraepithelial neoplasia lesions with increased proliferation and inflammation. Combined deletion of Eaf1 and Eaf2 in the murine model induced an increased incidence in mPIN lesions characterized by increased proliferation and CD3+ T cells and CD19+ B cells infiltration compared to individual deletion of either Eaf1 or Eaf2 in the murine prostate. These results suggest that EAF1 may play a tumor suppressive role in the prostate. Cooperation between EAF1 and EAF2 may be important for prostate maintaining prostate epithelial homeostasis, and concurrent loss of these two tumor suppressors may promote prostate tumorigenesis and progression.

| S-EPMC6593215 | biostudies-literature

Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

Project description:IntroductionHigh Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear.MethodsWe performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2:ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason patterns 3 and 4 foci, using microdissection and targeted deep-sequencing.ResultsA total of 32 tumor-specific mutated sites were successfully amplified and sequenced, including 25 truncal mutations and 7 mutations that were specific to either the Gleason pattern 3 or pattern 4 foci. All six HGPIN foci shared the same tumor-specific TMPRSS2:ERG fusion breakpoint, establishing that they were all clonally related to the adjacent invasive tumor. Among the 32 gene targets mutated in the invasive tumor, only mutation of the OR2AP1 gene, a truncal mutation, was found in a single focus of HGPIN. The remaining gene targets that were successfully sequenced were wild-type in all other HGPIN foci.DiscussionThis study demonstrates the feasibility of targeted mutation profiling of HGPIN lesions, which will be important to understand PCa tumorigenesis. The results in this case, showing a remarkable absence of truncal mutations in HGPIN lesions bearing the tumor-specific ERG fusion, indicate HGPIN lesions may be relatively stable genetically and argue against a stepwise clonal evolution model of HGPIN to PCa. Prostate 76:1227-1236, 2016. © 2016 Wiley Periodicals, Inc.

| S-EPMC5507580 | biostudies-literature

EAF2 loss induces prostatic intraepithelial neoplasia from luminal epithelial cells in mice.

Project description:Defining the cell of origin for prostatic carcinogenesis is fundamentally important for understanding the mechanisms leading to prostate cancer. Lineage tracing studies have demonstrated that luminal epithelial cells are capable of self-replication in multiple organs, including the adult murine prostate, and cell of prostate cancer origin studies have shown that while both the luminal and basal murine prostate epithelial cells are capable of neoplastic transformation, luminal cells are more efficient as the origin of prostate cancer. ELL-associated factor 2 (EAF2) is an androgen responsive tumor suppressive protein expressed by prostate luminal epithelial cells that is frequently down-regulated in primary prostate tumors. EAF2 knockdown induces prostate cancer cell proliferation and invasion in vitro and mice with Eaf2 deficiency develop epithelial hyperplasia and murine prostatic intraepithelial neoplasia (mPIN) lesions. Here, we utilized an Eaf2 knockout, PSA-CreERT2 transgenic model crossed with a fluorescent reporter line to show that Eaf2 deficiency induces mPIN lesions derived from the luminal cell lineage. These results suggest that PIN lesions in the Eaf2 knockout mouse were derived from prostate luminal epithelial cells, further suggesting that the prostatic luminal epithelial cell is the major origin of prostate carcinogenesis.

| S-EPMC7076293 | biostudies-literature

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