Abstract
The ETS transcription factor ETV1 is frequently overexpressed in aggressive prostate cancer, which is one underlying cause of this disease. Accordingly, transgenic mice that prostate-specifically overexpress ETV1 develop prostatic intraepithelial neoplasia. However, progression to the adenocarcinoma stage is stifled in these mice, suggesting that inhibitory pathways possibly preclude ETV1 from exerting its full oncogenic potential. Here we provide evidence that TGF-β/SMAD signaling represents such an inhibitory pathway. First, we discovered that ETV1 forms complexes with SMAD4. Second, SMAD2, SMAD3 and SMAD4 overexpression impaired ETV1’s ability to stimulate gene transcription. Third, TGF-β1 inhibited ETV1-induced invasion by benign RWPE-1 prostate cells. Fourth, increased expression of SMAD3 and SMAD4 was observable in prostates of ETV1 transgenic mice. Conversely, we found that ETV1 may enhance TGF-β signaling in PC3 prostate cancer cells, revealing a different facet of the ETV1/TGF-β interplay. Altogether, these data provide more insights into the regulation and action of ETV1 and additionally suggest that TGF-β/SMAD signaling exerts its tumor suppressive activity, at least in part, by curtailing the oncogenic potential of ETV1 in prostatic lesions.
Highlights
One unresolved question is why ETV1 transgenic mice did not progress from PIN to the adenocarcinoma stage
We identified SMAD4 as a novel interaction partner of ETV1 that can repress ETV1-mediated transcription, providing a mechanism by which transforming growth factor β (TGF-β) signaling may constrain ETV1’s oncogenic activity
This suggests a model whereby ETV1 overexpression in the prostate in part limits its own oncogenic potential by activating the tumor suppressive power of TGF-β; but upon SMAD4 downregulation or inactivating mutation, ETV1’s oncogenic activity becomes fully competent and this is needed for the progression of PIN to carcinoma in the prostate (Fig. 8)
Summary
One unresolved question is why ETV1 transgenic mice did not progress from PIN to the adenocarcinoma stage. A similar question related to the homozygous deletion of the tumor suppressor PTEN in the prostate of mice, which led to PIN, but only after a long latency induced adenocarcinomas that rarely metastasized[22,23]. Deletion of SMAD4 in addition to PTEN invariably resulted into the development of metastatic, lethal prostate cancer at an early age, whereas SMAD4 ablation on its own reportedly did not cause any prostatic lesions[24]. These data suggested that SMAD4 is a barrier that can prevent progression of prostate tumorigenesis. We explored if TGF-β and SMAD proteins might repress the oncogenic potential of ETV1
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