| First Author | Bjerke GA | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 3 | Pages | e92800 |
| PubMed ID | 24651496 | Mgi Jnum | J:215070 |
| Mgi Id | MGI:5604600 | Doi | 10.1371/journal.pone.0092800 |
| Citation | Bjerke GA, et al. (2014) Prostate cancer induced by loss of Apc is restrained by TGFbeta signaling. PLoS One 9(3):e92800 |
| abstractText | Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFbeta signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFbeta pathway by deleting the gene encoding the TGFbeta type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice. Prostate-specific Apc;Tgfbr2 mutants had a lower frequency of metastasis and survived significantly longer than Pten;Tgfbr2 double mutants. However, all Apc;Tgfbr2 mutants developed invasive cancer by 30 weeks of age, whereas invasive cancer was rarely observed in Apc single mutant animals, even by one year of age. Further comparison of the Pten and Apc models of CaP revealed additional differences, including adenosquamous carcinoma in the Apc;Tgfbr2 mutants that was not seen in the Pten model, and a lack of robust induction of the TGFbeta pathway in Apc null prostate. In addition to causing high-grade prostate intra-epithelial neoplasia (HGPIN), deletion of either Pten or Apc induced senescence in affected prostate ducts, and this restraint was overcome by loss of Tgfbr2. In summary, this work demonstrates that TGFbeta signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFbeta signaling exerts a general tumor suppressive effect in prostate. |
