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Breast cancer's many drivers
Date:6/20/2012

chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn't normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.

This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.

Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.

"This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway," said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. "That's important because this is one of the most frequently mutated pathways in human cancer, especially in women's cancers such as breast, ovarian, and endometrial cancer."

The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most "druggable."

In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.

"There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy," Toker said. "These are all experiments that are under way."

Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemic
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Contact: Nicole Davis
ndavis@broadinstitute.org
617-714-7152
Broad Institute of MIT and Harvard
Source:Eurekalert

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