title: Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases.
abstract: To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.forename: Chang-Jiun
authors.initials: CJ
authors.lastname: Wu
authors.forename: Mariela
authors.initials: M
authors.lastname: Jaskelioff
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Guocan
authors.initials: G
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Emma S
authors.initials: ES
authors.lastname: Labrot
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Jingfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Perry
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Liren
authors.initials: L
authors.lastname: Li
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D019098:Telomerase