title: Prostate cancer induced by loss of Apc is restrained by TGFβ signaling.
abstract: Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ 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 TGFβ pathway by deleting the gene encoding the TGFβ 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 TGFβ 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 TGFβ signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFβ signaling exerts a general tumor suppressive effect in prostate.
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Bjerke
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America; Department of Cytobiochemistry, University of Lodz, Lodz, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pietrzak
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Melhuish
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Bryce M
authors.initials: BM
authors.lastname: Paschal
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Wotton
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D006720:Homozygote; D053550:Keratin-10; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053550:Keratin-10; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D051059:PTEN Phosphohydrolase