title: Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint.
abstract: Improved clinical management of prostate cancer has been impeded by an inadequate understanding of molecular genetic elements governing tumor progression. Gene signatures have provided improved prognostic indicators of human prostate cancer. The TGF-β/BMP-SMAD4 signaling pathway, which induces epithelial-mesenchymal transition (EMT), is known to constrain prostate cancer progression induced by Pten deletion. Herein, cyclin D1 inactivation reduced cellular proliferation in the murine prostate in vivo and in isogenic oncogene-transformed prostate cancer cell lines. The in vivo cyclin D1-mediated molecular signature predicted poor outcome of recurrence-free survival for patients with prostate cancer (K-means HR, 3.75, P = 0.02) and demonstrated that endogenous cyclin D1 restrains TGF-β, Snail, Twist, and Goosecoid signaling. Endogenous cyclin D1 enhanced Wnt and ES cell gene expression and expanded a prostate stem cell population. In chromatin immunoprecipitation sequencing, cyclin D1 occupied genes governing stem cell expansion and induced their transcription. The coordination of EMT restraining and stem cell expanding gene expression by cyclin D1 in the prostate may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology, Medical Oncology, and Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Marco
authors.initials: M
authors.lastname: Crosariol
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000502:physiology*; D018450:Disease Progression; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012008:Recurrence; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human