Blocking these Myc proteins halts cell proliferation in the deadliest cancer of the female reproductive system, according to a presentation by University of California, Berkeley scientists at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.
In 30-60 percent of human ovarian tumors, MYC is overly active, or amplified, usually as a result of extra chromosomal copies of the cancer-causing gene.
The extra MYC encourages the ovarian cells to manufacture too much c-Myc, a protein that regulates other genes involved in cellular growth and proliferation. The presence of excessive c-Myc protein drives healthy cells down the cancer development pathway.
Using RNA interference (RNAi) to block c-Myc protein, Berkeley scientists, Tulsiram Prathapam and G. Steven Martin, treated lab cultures of human ovarian cancer cells that contained amplified MYC. RNAi's blocking of the c-Myc protein stopped the cancer cell cycle in its tracks.
But RNAi blocking of c-Myc protein in lab cultures in which the MYC gene was not experimentally amplified did not affect ovarian cancer cell growth.
The scientists suspect that even when c-Myc was blocked in non-amplified cells, other forms of the protein ⎯ L-Myc and N-Myc ⎯ likely were present and continued to maintain cell proliferation.
By using small interfering RNA (siRNA) to silence L-Myc and N-Myc, the researchers succeeded in shutting down the growth of the non-amplified MYC tumors.
These therapies also were applied to lab cultures of normal ovarian surface epithelial cells. Blocking all the Myc proteins in the normal cultures did not affect cell proliferation, perhaps because the RNAi and siRNA "therapies" are effective only when the MYC genes are abnormally active.
The scientists hope that their results may lead to a new approach to treating ovarian cancer, the most lethal cancer of the female reproductive system.
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They identified two types of genomic instability. One type occurs at the point where the cancer becomes invasive, leaving the milk duct system and going into surrounding tissues. The other is associated with repetitive structures called low copy repeats found in the genome itself, a finding not associated with genomic instability before, he said.
The low copy number repeats expose a particular defect in the repair mechanism for double stranded DNA. When that does not work, the genome can break apart and fuse again, this type aberrantly.
Even though the study deals with only one cell line, it has proved valuable, said Lee.
"It has raised some novel ideas about how these rearrangements can affect the DNA repair pathways of the cell. We have a conundrum. You have these breaks in the DNA that affect the DNA repair proteins that are supposed to repair the breaks.
He said plans are already underway to study more cell lines along with individual breast tumors to obtain a more complete picture of the DNA changes that are involved.
Milosavljevic points out that this study is one of several that have appeared this year. For example, the BCM Human Genome Sequencing Center also took part in determining the sequences of glioblastoma (a brain cancer) and lung adenocarcinoma. All occurred under the umbrella of the Cancer Genome Atlas Project funded by the National Institutes of Health. These studies, along with others, prove the value of that more global project, he said.
"Our aim with this work is to establish a bench mark to validate the next generation of sequencing technologies and the whole method that will lead to new biologically significant discoveries," Milosavljevic said.
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