Genetic interaction between Tmprss2-ERG gene fusion and Nkx3.1-loss does not enhance prostate tumorigenesis in mouse models

3Citations
Citations of this article
12Readers
Mendeley users who have this article in their library.

Abstract

Gene fusions involving ETS family transcription factors (mainly TMPRSS2-ERG and TMPRSS2-ETV1 fusions) have been found in ∼50% of human prostate cancer cases. Although expression of TMPRSS2-ERG or TMPRSS2-ETV1 fusion alone is insufficient to initiate prostate tumorigenesis, they appear to sensitize prostate epithelial cells for cooperation with additional oncogenic mutations to drive frank prostate adenocarcinoma. To search for such ETS-cooperating oncogenic events, we focused on a well-studied prostate tumor suppressor NKX3.1, as loss of NKX3.1 is another common genetic alteration in human prostate cancer. Previous studies have shown that deletions at 8p21 (harboring NKX3.1) and 21q22 (resulting in TMPRSS2-ERG fusion) were both present in a subtype of prostate cancer cases, and that ERG can lead to epigenetic silencing of NKX3.1 in prostate cancer cells, whereas NKX3.1 can in turn negatively regulate TMPRSS2-ERG fusion expression via suppression of the TMPRSS2 promoter activity. We recently generated knockin mouse models for TMPRSS2-ERG and TMPRSS2-ETV1 fusions, utilizing the endogenous Tmprss2 promoter. We crossed these knockin models to an Nkx3.1 knockout mouse model. In Tmprss2-ERG;Nkx3.1+/- (or-/-) male mice, although we observed a slight but significant upregulation of Tmprss2-ERG fusion expression upon Nkx3.1 loss, we did not detect any significant cooperation between these two genetic events to enhance prostate tumorigenesis in vivo. Furthermore, retrospective analysis of a previously published human prostate cancer dataset revealed that within ERG-overexpressing prostate cancer cases, NKX3.1 loss or deletion did not predict biochemical relapse after radical prostatectomy. Collectively, these data suggest that although TMPRSS2-ERG fusion and loss of NKX3.1 are among the most common mutational events found in prostate cancer, and although each of them can sensitize prostate epithelial cells for cooperating with other oncogenic events, these two events themselves do not appear to cooperate at a significant level in vivo to enhance prostate tumorigenesis.

Figures

  • Fig 1. Nkx3.1-loss modestly increases the Tmprss2 promoter activity in vivo. A. Progressive Nkx3.1 transcript loss was confirmed in wild type (black) and heterozygous (dark gray) and homozygous (light gray) Nkx3.1 knockout mice by real-time RT-PCR (left). Immunohistochemical (IHC) staining of anterior prostates (APs) using a mouse-specific Nkx3.1 antibody also validated Nkx3.1 protein loss.B. Real-time RT-PCR showing slight but statistically significant
  • Fig 2. HeterozygousNkx3.1-loss does not strongly cooperate with Pten-loss and Tmprss2-ERG expression. A. Representative anterior prostate (AP) histology of male mice with the indicated combinations of Nkx3.1+/-, Pten+/-, and T-ERG knockin. Note HG-PIN lesions developed in all prostate lobes of TERG;Pten+/- and T-ERG;Pten+/-;Nkx3.1+/-males due to cooperation between Pten+/- and T-ERG. Representative HG-PIN lesions developed in the APs of TERG;Pten+/- and T-ERG;Pten+/-;Nkx3.1+/-males are shown (red arrows). Scale bars represent 100 μm. B. Histology summary of aged Pten+/- (left) and Pten+/-;Nkx3.1+/- (right) male mice with or without the T-ERG knockin allele. Notable cooperation was detected with T-ERG (p = 0.05 under the Pten+/background and p = 0.04 under the Pten+/-;Nkx3.1+/- background). HG-PIN in any prostate lobe was diagnosed by a trained rodent pathologist.
  • Fig 3. TotalNkx3.1-loss does not cooperate with Tmprss2-ERG gene fusion to promote prostate tumorigenesis. A. Representative anterior lobe (AP) histology of Nkx3.1-/- (left) and T-ERG;Nkx3.1-/- (right) mouse prostates stained with H&E. Scarce pleomorphic nuclei are evident (red arrows). Scale bars represent 100 μm. B.Graphical summary of histological findings of Nkx3.1-/- and T-ERG;Nkx3.1-/- male mice. There was no significant difference in AP
  • Fig 4. NKX3.1-loss in patients harboring ERG rearrangements is not predictive of biochemical relapse. Patient data from Taylor et al. [29] was used to compare via Kaplan-Meier analysis the disease-free survival of patients overexpressing ERG, which is highly predictive of harboring TMPRSS2-ERG fusion. Within this 'ERGup' cohort, patients who exhibited NKX3.1 downregulation (red line, n = 4) compared to those who expressed normal levels of NKX3.1 (blue line, n = 65) were not more likely to display biochemical relapse. Logrank test p value was 0.35. Analysis performed using the cbioportal software [31].

References Powered by Scopus

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal

11197Citations
N/AReaders
Get full text

Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer

3312Citations
N/AReaders
Get full text

Integrative Genomic Profiling of Human Prostate Cancer

3036Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Genetics and biology of prostate cancer

509Citations
N/AReaders
Get full text

Genetically engineered mouse models of prostate cancer in the postgenomic era

40Citations
N/AReaders
Get full text

Protocols for studies on TMPRSS2/ERG in prostate cancer

2Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Linn, D. E., Bronson, R. T., & Li, Z. (2015). Genetic interaction between Tmprss2-ERG gene fusion and Nkx3.1-loss does not enhance prostate tumorigenesis in mouse models. PLoS ONE, 10(3). https://doi.org/10.1371/journal.pone.0120628

Readers over time

‘15‘17‘18‘19‘20‘21‘2300.751.52.253

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 4

67%

Professor / Associate Prof. 1

17%

Researcher 1

17%

Readers' Discipline

Tooltip

Agricultural and Biological Sciences 4

57%

Medicine and Dentistry 1

14%

Biochemistry, Genetics and Molecular Bi... 1

14%

Chemistry 1

14%

Save time finding and organizing research with Mendeley

Sign up for free
0