JUNB promotes the survival of Flavopiridol treated human breast cancer cells
Mellissa Hicks1, Qiuping Hu1, Erin Macrae2
1Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA.
Abstract:
Chemotherapy resistance is a major obstacle to achieving durable progression-free-survival in breast cancer patients. Identifying resistance mechanisms is crucial to the development of effective breast cancer therapies. Immediate early genes (IEGs) function in the initial cellular reprogramming response to alterations in the extracellular environment and IEGs have been implicated in cancer cell development and progression. The purpose of this study was to investigate the influence of kinase inhibitors on IEG expression in breast cancer cells. The results demonstrated that Flavopiridol (FP), a CDK9 inhibitor, effectively reduced gene expression. FP treatment, however, consistently produced a delayed induction of JUNB gene expression in multiple breast cancer cell lines. Similar results were obtained with Sorafenib, a multi-kinase inhibitor and U0126, a MEK1 inhibitor. Functional studies revealed that JUNB plays a pro-survival role in kinase inhibitor treated breast cancer cells. These results demonstrate a unique induction of JUNB in response to kinase inhibitor therapies that may be among the earliest events in the progression to treatment resistance.
Insights
Kinase inhibitors can trigger a delayed JUNB gene response in breast cancer cells, potentially driving treatment resistance. Understanding this immediate early gene (IEG) mechanism is key to developing new therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemotherapy resistance impedes progression-free survival in breast cancer.
- Identifying resistance mechanisms is crucial for effective cancer therapies.
- Immediate early genes (IEGs) are involved in cancer cell progression.
Purpose of the Study:
- To investigate the impact of kinase inhibitors on IEG expression in breast cancer cells.
- To explore the role of JUNB in breast cancer cell survival during kinase inhibitor treatment.
Main Methods:
- Treatment of breast cancer cell lines with kinase inhibitors (Flavopiridol, Sorafenib, U0126).
- Analysis of gene expression, focusing on JUNB.
- Functional studies to determine JUNB's role in cell survival.
Main Results:
- Flavopiridol (a CDK9 inhibitor) reduced gene expression but induced delayed JUNB expression.
- Similar delayed JUNB induction was observed with Sorafenib and U0126.
- JUNB was found to play a pro-survival role in kinase inhibitor-treated breast cancer cells.
Conclusions:
- Kinase inhibitor therapy can uniquely induce JUNB expression in breast cancer cells.
- This JUNB induction may be an early event in the development of treatment resistance.
- Targeting JUNB could be a potential strategy to overcome kinase inhibitor resistance.
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