IKBKE gene amplification is seen loud and clear in breast cancer tumors!

News Article:

Kirkley, Sharon. (2007, June 15). Cancer fight may have key gene to target; Breast Cancer Research. National Post Canada.

Primary Scientific Article:
Boehm, Jesse S. et. al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol. 129, pp. 1065-1079

Articles citing primary article:
1. Adelaide, Jose. et. al (2007). Integrated Profiling of Basal and Luminal Breast Cancers. Cancer Research Vol. 67, pp. 11565-11575

2. Liu, Dingxie, Liu Zhi, Jiang David, Dackiw, Alan P., and Xing Mingzhao. et. al (2007). Inhibitory Effects of the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 on the Proliferation and Tumor Growth of Thyroid Cancer Cells with BRAF or RAS Mutations. Journal of Clinical Endocrinology & Metabolism Vol. 92, pp. 4686-4695

Summary:
Researchers found that the onset and survival of breast cancer cells is in part due to a mutation in IKBKE that resulted in gene amplification. Mutated IKBKE is an oncogene that results in uncontrolled cell proliferation. Prior to this research little was known in regards to how IKBKE could cause cancer or why the over activation of NFkB pathways seemed to be a common characteristic of breast cancer. The discovery found in the article is important because it could potentially lead to effective breast cancer drugs and therapies. Breast cancer is the most common form of cancer found in women.

The researchers used a combination of various techniques to find and isolate the gene that was causing cancer. Their initial goal was unrelated to the study of IKBKE. They first set out to study if two pathways commonly associated with normal cell cycle control and cancer RAS-MAPK and P13K-AKT could be hyper activated resulting in uncontrolled cell proliferation without there being a mutation in RAS. RAS is a proto-oncogene that activates both pathways. In order to study this the scientists created sixteen cell lines expressing all possible combinations of the three mutations, other then that of RAS, that were known to cause problems in the cell signaling pathways of MAPK and P13K. Scientists closely monitored the number of initial mutations and copies of those mutations so that all cell cultures would be alike with the exception of the initial mutation they had been given. Results showed that tumor growth would appear when both RAS-MAPK and the P13K- AKT pathways were over activated and communicated with each other. This activity would occur via co-expression of MEK that would activate the MAPK pathway and myr-AKT expression that would activate the P13K pathway. Since both pathways generate signals that produce transcription factors via a signal cascade due to phosphorylation, the scientists then set out to find out what kinases would have the ability to affect signal transduction in one or both pathways and possibly contribute in the aforementioned co-expression. In order to pinpoint kinases scientists then created cell lines that expressed MEK and myr-AKT kinases to ORF’s, open reading frames to see if they would induce cancer. As a result of this experiment four kinases were identified. Unfortunately, with the results of this experiment another question emerged. Were any if not all of these kinases over expressed in human cancers?

In order to test whether or not any or all of these kinases were over expressed in human cancers, regions of cancer cell tumors that presented single nucleotide polymorphisms that may have resulted in a mutation that encoded, for more kinases then it should have, were examined. One hundred seventy nine cell lines were examined in total and from all of those the only gene that was amplified was IKBKE. In order to narrow IKBKE relationship to cancer in general and be able to draw conclusions between the IKBKE mutation and specific cancers, a CGH was performed on 30 breast tumors of different stages to see if a mutation in IKBKE could be a specific cause of breast cancer. The procedure CGH simply involves screening tumor samples for genetic changes showing patterns of copy number changes i.e. gene amplification. This procedure found a mutation on chromosome 1q32. Unfortunately, however, these results only led to the emergence of another question. Could increased levels of IKBKE by itself cause cancer? What would happen to the cell if IKBKE was under expressed i.e. suppressed?

The scientists chose to create cell lines that expressed gene amplification of IKBKE wild type to test whether or not increased levels of IKBKE alone was enough to cause cancer. Upon observation of theses cell lines the researchers noted that an increase in levels of IKBKE led to an increase in transcription via activation of the NFkB pathway that resulted in an increase in protein levels that promoted cell proliferation. When IKBKE was inactivated within the same cell lines breast cancer cells were unable to proliferate. In order to further test if the activation of NFkB was necessary in cell transformation, the scientists mutated the NFkB pathway so that it would be unable to phosphorylate and initiate internal signals. These cell lines when compared to those with increased levels of IKBKE and a functioning NFkB pathway experienced much less cancer formation. Therefore IKBKE normally functions as a kinase but when expressed in high levels within cells it can function as an oncogene that promotes cell proliferation via activation and communication of the NFkB pathway.

The primary article as to be expected provides more information and details about the approaches and methods the researchers used to discover that the presence of IKBKE in excess within cells had the capability of inducing cellular transformation resulting in cancer. While the news article simply provides readers with basic information regarding the fact that the scientists were studying kinases to see if the presence of any in excess could be attributed to cancer and discovered that IKBKE seemed to present in high amounts amongst the breast cancer tumors they examined. Utilizing this comparison it is obvious that the primary article is more trustworthy. Both articles, however, due a good job in describing how the discovery could in the near future lead to more effective breast cancer treatments and therapies thereby improving the lives of thousands of women. In this way both articles make me feel hopeful about the future of cancer research.

Questions:
How would researchers go about trying to produce a drug that triggers the mutation that produces excess IKBKE?
How many other kinases are known to play a part in cellular transformation?