New cellular flaw found in some virulent breast cancers

Overactive growth controller could become drug target

Researchers at Dana-Farber Cancer Institute have identified a molecular interaction that triggers a particularly aggressive form of breast cancer, and suggest that attacking this target with selective drugs might improve treatment.

In the January issue of Cancer Cell, a team led by Qunyan Yu, MD, and Peter Sicinski, MD, PhD, of Dana-Farber report that the interaction of a certain mutated oncogene and the newly described growth control flaw is seen in about 10 percent of breast cancers – and the deadliest ones.

The cancer results from a cascade of molecular events. The overproduction of a common protein, cyclin D1, hyperstimulates a growth switch, CDK4 kinase, causing it to unleash a virulent proliferation of cancer cells and creating a tumor with a very poor prognosis.

"The development of cancer drugs like Gleevec and Iressa have shown that it is possible to block the action of kinases," said Sicinski, "so we hope that these findings will stimulate interest in developing drugs to block CDK4 as a targeted approach to treating this very aggressive cancer."

Breast cancers composed of cells that contain both the overactive cyclin D1- CDK4 switch and a mutated cancer-causing gene ErbB-2 (also known as HER2) are extremely difficult to treat. In one recent study, the seven-year survival rate for women with this subgroup of breast cancers was only about 13 percent.

Clinicians have had some recent success in treating breast cancers with a mutated ErbB-2 gene, which are also referred to as being HER2-positive. The targeted therapy Herceptin blocks the mutation, improving the outlook for such patients, though it doesn't work in all cases. Sicinski said that a CDK4 inhibitor might be used in combination with Herceptin to provide further benefit in these patients.

If a drug to block CDK4 proved feasible, Sicinski said, it may be possible to test women's breast tumors for the presence of the overactive kinase, and then treat those patients with the inhibitor. "We are going to see in the next five years a movement away from treating all tumors with the same drugs, and instead match specific drugs to tumors based on their molecular characteristics," said Sicinski, who is also an associate professor of pathology at Harvard Medical School.

Cyclin D1 is one of a family of proteins that help regulate a cell's passage through its cycle of rest and growth. Overabundance of cyclin D1 has been observed in many cancers. For a number of years, Sicinski's laboratory has carried out a series of experiments to determine whether the protein has an important normal function, or whether it could be blocked by designer drugs to treat breast cancer without harming the patient.

Previously, mice engineered to lack cyclin D1 were found to be highly resistant to certain breast cancers, and other experiments showed that mice in which the cyclin D1 gene had been inactivated developed into more or less normal adults.

However, said Sicinski, it is difficult to design a drug to neutralize the action of a protein like cyclin D1. In the most recent experiments, the research team's objective was to determine precisely which of cyclin D1's several different functions was responsible for causing breast cancer.

By creating laboratory mice with different combinations of genes present or missing, the researchers were able to isolate the various cyclin D1 activities. They demonstrated that cyclin D1's ability to activate CDK4 kinase activity is what causes the aggressive cancers, and that this same activity is required for the cancer to continue to grow.

Additional experiments reported in another Cancer Cell paper found that bioengineered mice in which cyclin D1 could not activate CDK4 kinase were developmentally normal and highly resistant to ErbB-2-caused breast cancers, demonstrating that blocking CDK4 was not harmful to the mice. That research was carried out by scientists at Tufts-New England Medical Center, Harvard Medical School, and Massachusetts Eye and Ear Infirmary, together with Sicinski.

The identification of the cyclin D1-CDK4 kinase pathway is important and could pave the way to new therapies, says Sicinski, adding that while it would be difficult to design a drug to inhibit the action of a protein like cyclin D1, blocking a kinase is significantly easier.

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The study was funded in part by grants from the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.

The paper's other authors are from Linkoping University, Linkoping, Sweden; Biogen Idec, Cambridge, Mass.; and Northwestern University, Chicago.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.


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