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Published on: September 19, 2018
The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation
Nomeda Girnius1, Yvonne Jk Edwards1, David S Garlick2
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
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.
Insights
Defects in the cJUN NH2-terminal kinase (JNK) pathway unexpectedly promote breast cancer. Loss of JNK signaling causes genomic instability, leading to tumor initiation and development in mice.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Breast cancer is a leading malignancy in women.
- Genomic analysis reveals frequent loss-of-function mutations in the cJUN NH2-terminal kinase (JNK) pathway in breast cancer.
- The role of JNK signaling in tumor development was previously unclear due to its association with cell proliferation.
Purpose of the Study:
- To investigate the role of JNK signaling in breast cancer development.
- To determine if JNK deficiency contributes to tumor initiation or progression.
Main Methods:
- Examined the effects of JNK deficiency in murine breast epithelium.
- Assessed genomic instability and tumor formation in a mouse model.
Main Results:
- Loss of JNK signaling led to genomic instability and breast cancer development in mice.
- JNK deficiency resulted in early neoplasia and rapid tumor formation.
- JNK's tumor suppressive function is critical for preventing tumor initiation, not for inhibiting established tumor growth.
Conclusions:
- Defects in the JNK pathway act as driver mutations promoting genome instability.
- JNK signaling is essential for preventing breast tumor initiation.
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