Tumorigenesis requires accumulation of genetic and epigenetic alterations, some of which drive tumor initiation. "Oncogene addiction" describes the phenomenon that (1) well-established cancers are dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype and that (2) withdrawal of the single oncogenic event leads to growth arrest and/or cancer regression.
While oncogene addiction has been experimentally validated in advanced tumor models, its role in tumor precursors has not been investigated. We utilized the requirement of Forkhead box A1 (Foxa1) for transcriptional activation of the Upk2-promoter to temporally control the expression of Upk2-HRAS* oncogene, an inducer of urothelial hyperplasia in transgenic mice. Inducible homozygous knockout of Foxa1 in Upk2-HRAS*/UBC-CreERT2/Foxa1loxp/loxp mice results in reduced HRAS* levels. This led to a marked reduction of urothelial proliferation as evidenced by urothelial thinning, degenerative changes such as intracellular vacuole formation, and reduced Ki67 expression. Reduced proliferation did not affect basal, Krt14-positive cells, supporting the fact that Foxa1-regulated Upk2-HRAS* expression occurs primarily in supra-basal cells. Our results indicate that maintenance of urothelial hyperplasia in Upk2-HRAS* mice depends on continuous expression of Foxa1 and activated HRAS, and that mutated receptor tyrosine kinases, FOXA1 and/or other downstream effectors may mediate oncogene addiction in urothelial hyperplasia.
Scientific reports. 2019 Jan 22*** epublish ***
Christopher H Yee, Zongyu Zheng, Lauren Shuman, Hironobu Yamashita, Joshua I Warrick, Xue-Ru Wu, Jay D Raman, David J DeGraff
Department of Pathology and Laboratory Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA, USA., Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY, USA., Department of Surgery, Division of Urology, The Pennsylvania State University, College of Medicine, Hershey, PA, USA., Department of Pathology and Laboratory Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA, USA. .