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Genetic interaction between Tmprss2-ERG gene fusion and Nkx3.1-loss does not enhance prostate tumorigenesis in mouse
Douglas E Linn1, Roderick T Bronson2, Zhe Li1
1Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States of America.
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.
Insights
Despite being common in prostate cancer, TMPRSS2-ERG fusions and NKX3.1 loss do not significantly cooperate to drive tumor development in mice or predict relapse in human patients.
Area of Science:
- Urology
- Oncology
- Molecular Biology
Background:
- Gene fusions involving ETS transcription factors, such as TMPRSS2-ERG, are prevalent in prostate cancer.
- Loss of the NKX3.1 tumor suppressor is also a common genetic alteration in prostate cancer.
- Both events individually sensitize prostate cells for tumorigenesis but their cooperative role is unclear.
Purpose of the Study:
- To investigate the in vivo cooperation between TMPRSS2-ERG/ETV1 fusions and NKX3.1 loss in prostate tumorigenesis.
- To determine if combined genetic alterations predict clinical outcomes in prostate cancer patients.
Main Methods:
- Generated knockin mouse models for TMPRSS2-ERG and TMPRSS2-ETV1 fusions.
- Crossed these models with Nkx3.1 knockout mice to assess tumor development.
- Analyzed a human prostate cancer dataset for correlations between ERG expression, NKX3.1 status, and biochemical relapse.
Main Results:
- Loss of Nkx3.1 showed a slight upregulation of Tmprss2-ERG expression in mice but did not enhance prostate tumorigenesis.
- NKX3.1 loss or deletion did not predict biochemical relapse in ERG-overexpressing human prostate cancer cases.
- These two common prostate cancer events do not significantly cooperate in vivo.
Conclusions:
- TMPRSS2-ERG fusion and NKX3.1 loss, despite their individual roles in prostate cancer initiation, do not exhibit significant cooperative oncogenic activity.
- The absence of cooperation suggests distinct or parallel pathways in prostate tumorigenesis involving these specific alterations.
