title: v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1.
abstract: Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics, and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Patients with prostate cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 4.35). Cyclin D1, therefore, serves as a transducer of v-Src-mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex. Cancer Res; 76(22); 6723-34. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shengqiong
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Agnese
authors.initials: A
authors.lastname: Di Rocco
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Hawkins
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics University of California, Los Angeles, California.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stoyanova
authors.affiliation: Faculty of Pharmacy, Nutrition, and Health Science, University of Calabria, Arcavacata, Rende CS, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Pharmacology and Physiology and Laboratory Medicine, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Richard.Pestell@jefferson.edu.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C544766:TROP2 protein, mouse; D019938:Cyclin D1; D019061:src-Family Kinases