They say that levels of the protein produced by this suspected oncogene, known as atypical protein kinase C iota (PKCi), in combination with a second protein, Cyclin E, strongly predict outcome in non-serous ovarian cancer, which accounts for 40 percent of ovarian cancer cases.
They further report PKCi is over-expressed in serous ovarian cancer, which makes up the remaining 60 percent of ovarian cancer cases.
Based on these findings, published in the early edition of the Proceedings of the National Academy of Sciences (PNAS), the week of Aug. 22, 2005, the researchers suggest that PKCi as well as the second protein, Cyclin E, could be used as a powerful predictive test for non-serous ovarian cancer. They also say that an agent that inhibits PKCi might offer a novel therapy for both forms of the cancer, which is difficult to treat in advanced stages.
This study is the first to find that PKCi plays a role in ovarian cancer, says the study's principal investigator Gordon Mills, M.D., Ph.D., a professor and chair of the Department of Molecular Therapeutics.
More than that, he says, "this is the first direct proof that over-expression of PKCi is sufficient to produce proliferation in ovarian cancer, and thus acts as an oncogene."
Mills and the research team, which includes investigators from Lawrence Berkeley National Laboratory and the University of Wisconsin, believe that over-expression of PKCi triggers excess production of Cyclin E, which is known to play a role in cancer growth.
PKCi is a member of a family of PKC kinase proteins that regulates cell-to-cell communication and spatial orientation. While some members of this large family have been associated with cancer, PKCi had not before this study.
Researchers say that PKCi and Cyclin E together contribute to the aggressiveness of ovarian cancer because high levels of the protein are associated with reduced survival. "This is the strongest predictive combination of markers to determine behavior of ovarian cancer yet found," Mills says.
Studying more than 400 tumor biopsies, they found PKCi over-expression in all samples of serous ovarian cancer, and that elevated levels of PKCi and Cyclin E corresponded to a worsening prognosis in women with non-serous ovarian cancer.
Specifically, researchers found that patients with non-serous ovarian cancer whose tumor samples showed low levels of the protein had a chance of long-term survival that was greater than 85 percent. But the chance of long-term survival in patients whose cancer showed high levels of both proteins fell to less than 15 percent.
Mills, who heads M. D. Anderson's Kleberg Center for Molecular Markers, says the findings represent a case in which "the patient's tumor is teaching us what is important.
"Cancer is a disease of genes," he says. "If we can understand what the genetic aberrations are in cancer, and how they work together to cause a cancer or change its progression, then we can develop better ways of identifying a prognosis, predict response to therapy and identify new targets."
To let the tumor "talk," researchers used a technique known as comparative genomic hybridization which measured changes at the DNA level globally in tumors. It reviewed and compared the human genome in normal versus cancerous cells and found an area of constant genomic change in over 200 samples of ovarian cancer. Further probing found an area on chromosome 3 that was abnormal in the majority of ovarian cancer patients, Mills says.
They identified the PKCi gene as potentially contributing to this change and then turned to a "model organism," the fruit fly, to understand why PKCi could contribute to ovarian cancer. Fruit flies are used in this kind of research, Mills says, because "85 percent of all known human cancer genes have a corresponding gene in these organisms."
Researchers found that in fruit flies, PKCi increased the levels of Cyclin E and cell proliferation. "We then went back to our patient samples and found that those with low levels of PKCi and Cyclin E have a remarkably good outcome, while the opposite is true for higher levels," Mills says. "That offers us both a hope that PKCi can be used as a potent predictive test as well as a possible new way to treat the cancer."
The study was supported by grants from the National Cancer Institute and the Department of Energy. Co-authors include, from M. D. Anderson: first author Astrid Eder, Ph.D., and Xiaomei Sui, Daniel Rosen, Laura Nolden, Debra Smith, Kwia Wa Cheng, Ph.D., John Lahad, Jinsong Liu, M.D., Ph.D., Georg Halder, Ph.D., and Gordon Mills, M.D., Ph.D. Major outside collaborators included Joe Gray, Ph.D., from Lawrence Berkeley National Laboratory, and Jerry Ying, Ph.D., from the University of Wisconsin, Madison.
Journal
Proceedings of the National Academy of Sciences