The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation.

Nomeda Girnius,David S Garlick,Yvonne Jk Edwards,Roger J Davis

doi:10.7554/elife.36389

Abstract

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as 'driver' mutations that promote genome instability and tumor initiation.

Highlights

Breast cancer is the most frequently diagnosed tumor in women (Siegel et al, 2015)
The results presented by Girnius et al show that genetic changes which inactivate the JNK pathway can drive the development of breast cancer
To test whether JNK pathway disruption influences breast cancer development, we examined the effect of JNK-deficiency in the mammary epithelium

Summary

Introduction

Breast cancer is the most frequently diagnosed tumor in women (Siegel et al, 2015). The etiology of breast cancer has been studied in detail, but the causes of breast cancer remain incompletely understood. It is established that familial breast cancers result from germ-line mutations that increase the risk of cancer development (Afghahi and Kurian, 2017). Examples of inherited mutations that can cause breast cancer predisposition include ATM, BRCA1/2, CDH1, CHEK2, NBN, and TP53. Sporadic mutation of these and other genes promote the development of non-familial breast cancer (Hanahan and Weinberg, 2011). Changes in the tumor genome are important for breast cancer development (Hanahan and Weinberg, 2011)

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