The oncogene addiction model occurs when cancer cells become dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype. Withdrawal of the oncogenic signal leads to the regression of cancer. The role of oncogenic addiction in precursor lesions such as hyperplasia is not well understood. A recent study by Yee et al.  in Scientific Reports examined the interaction between Forkhead box A1 (FOXA1), a transcriptional activator of the Upk2-promoter in controlling the expression of oncogenic HRAS to induce urothelial hyperplasia in transgenic mice.1 By knocking out FOXA1, the investigators simulated oncogenic HRAS withdrawal. This resulted in a significant reduction of urothelial proliferation consistent oncogenic addiction to HRAS.

Interestingly, the investigators found that reduced proliferation did not affect basal cells indicating that the regulation of oncogenic HRAS by Upk2 occurs mainly in luminal cells. These results demonstrate the dependence of urothelial hyperplasia on the continuous expression of Foxa1 and activated HRAS in this model.

This important study adds to our understanding of the events that result in oncogenic addiction in urothelial hyperplasia. Additional studies characterizing the molecular events that occur in normal urothelium and precursor lesions such as hyperplasia have the potential for improving early-detection and for designing strategies to prevent progression.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

1. Yee CH, Zheng Z, Shuman L, Yamashita H, Warrick JI, Wu XR, Raman JD, DeGraff DJ. Maintenance of the bladder cancer precursor urothelial hyperplasia requires FOXA1 and persistent expression of oncogenic HRAS. Sci Rep. 2019 Jan 22;9(1):270. doi: 10.1038/s41598-018-36720-6.

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