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Genetic Studies Expose Instigators of Aggressive Breast Tumors

Summary

Triple-negative tumors lack three traits that can be targeted by available breast cancer treatments. But new findings suggest treatment possibilities for these aggressive cancers may be at hand.

Researchers have just discovered an important molecular cop on the cancer beat: Take the cop off the job, they have found, and a gang of cancer-promoting troublemakers run amok.

According to the new research, that is what happens in some cases of triple-negative breast cancer, an aggressive type of tumor that accounts for about 20 percent of breast malignancies. Triple-negative tumors are so named because unlike other breast cancers, they fail to test positive for any of three traits that can be targeted by available treatments. But now, based on the findings from Howard Hughes Medical Institute (HHMI) investigator Stephen Elledge and colleagues, treatment possibilities for these types of cancer may be at hand.

This gives hope to some people who really didn’t have many treatment choices. That’s a real positive outcome from some very basic research.

Stephen J. Elledge

Elledge says the latest findings stem from applying genetic tools–including some he developed with HHMI investigator Gregory Hannon of Cold Spring Harbor Laboratory— that have helped researchers understand how cancer is spawned and how it might be stopped. By identifying and studying the cancer cop, a type of molecule called a tyrosine phosphatase, the researchers have also identified some of the specific troublemakers, or the tyrosine kinases, that the cop restrains. The research is published in the March 4, 2011, issue of the journal Cell.

As it turns out, a few of those kinases are familiar suspects—molecules such as HER2 and EGFR that are targets of established cancer treatments. “The exciting thing is that there are existing inhibitors to a lot of these kinases,” says Elledge, a professor of genetics and medicine at Harvard Medical School’s Department of Genetics. For instance, inhibitors of EGFR include erlotinib (marketed as Tarceva by Genentech), used to treat some lung and pancreatic cancers, and cetuximab (marketed as Erbitux by ImClone), used for some colorectal cancers as well as head and neck cancers. “The big breakthrough in cancer research in the last several years has been finding these inhibitors.” he says. “And they are some of the best targeted therapies because they have fewer side effects than many standard chemotherapies.”

Because the tyrosine phosphatase cop keeps a lid on multiple kinases, it’s likely that a combination of medicines will be needed to effectively attack malignancies such as triple-negative breast cancer, the scientists note. Nevertheless, since various kinase inhibitors have already been deemed safe and are on the market, the research could quickly lead to a clinical trial to test their efficacy against triple-negative tumors.

“Seldom can you imagine an existing therapy for something that was previously intractable,” Elledge says. “This gives hope to some people who really didn’t have many treatment choices. That’s a real positive outcome from some very basic research.”

The new research—with essential contributions from Thomas Westbrook, who worked in Elledge’s lab and is now at Baylor College of Medicine in Houston, where much of the work was done—used a genetic screen to identify a molecule called PTPN12 as the tyrosine phosphatase that could limit kinase activity. The gene that governs production of PTPN12 is frequently deleted, mutated or turned off in triple-negative breast cancers and probably in many lung tumors, Elledge says, adding that scientists now can search for this vulnerability—the absence of PTPN12—in other types of tumors as well.

The researchers also are developing profiles of other good guys and bad guys in the PTPN12 neighborhood. For instance, PTPN12 is regulated by a gene called REST, which Elledge’s lab previously identified as a tumor suppressor. “We’re actually building a whole pathway here,” he says.

Based on their identification of the kinases, the researchers found they could predict which kinase inhibitors would be effective against human triple-negative breast cancers in mice. “Treating the mice with a combination of two inhibitors [lapatinib and sunitinib] was very robust in slowing down and reversing tumor growth,” says Elledge, who is also a professor in the Division of Genetics at Brigham and Women’s Hospital in Boston. Although the therapies on the market are not generally considered cures, he notes, they do extend patients’ lives—and perhaps, in combination with some new drug in the future, could prove curative.

The researchers next hope to figure out whether other phosphatases behave like PTPN12, and to identify all the kinases that promote cancer in the absence of PTPN12. The scientists also are systematically looking for other genes that quell tumor initiation and development.

Scientist Profile

Investigator
Brigham and Women's Hospital
Genetics, Molecular Biology

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