Herceptin targets the protein Her2 (a human epidermal growth factor receptor), which is produced in excess in some aggressive breast cancer tumors. The new study shows that the mouse version of the receptor protein, called erbB2, is needed for proper myocardial cell function.

"It was possible that Herceptin triggered cardiac malfunction by a number of mechanisms, but now it appears that the drug's direct action on erbB2 is the culprit [in mice]," said Kuo-Fen Lee, senior author of the study.

Lee noted that it should be possible to engineer new generations of drugs that would have a significantly less deleterious effect on heart function. "To do that we need to know more about the role of erbB2 in both cancer and heart cells," he said.

In the study, researchers engineered mice that would stop making erbB2 after birth selectively in heart tissue in order to avoid the problem earlier researchers faced that mice lacking erbB2 completely would not come to term due to myriad developmental defects.

Hearts from mice ages one to six months displayed clear signs of cardiomyopathy similar to those observed in Herceptin-related cardiac dysfunction.

"The enlarged heart and impaired contraction of these erbB2 mutant mice point to an unsuspected cardioprotective role for the secreted protein, neuregulin, that stimulates this receptor," said co-author Ken Chien.

Other physiological measurements also indicated compromised cardiac function in the mice. Myocardial cells were less elastic than normal and therefore less effective in contraction and relaxation.

In addition, the erbB2 mutant mice were more susceptible than their normal counterparts to stress. They were less able to recover from tightening of the aorta that resulted in hypertension.

Almost all women who receive Herceptin also receive or have received other chemotherapeutic drugs, particularly anthracyclines. Because concurrent Herceptin and anthracycline treatment increases cardiac dysfunction in patients, Lee and his colleagues examined the effects of anthracyclines on the erbB2 mutant mice.

They found that myocardial cells from the mutant mice were much more sensitive to adriamycin at drug levels resembling those in patients undergoing treatment. "Therefore, it appears that the loss of erbB2 function caused by Herceptin makes cardiac muscle more susceptible to anthracycline toxicity," said Lee.

"This mouse model will help us identify new mechanisms to protect patients from Herceptin cardiomyopathy and thereby allow more aggressive and early use of Herceptin for a broad range of human cancers," Chien said.