Cause of heart side effects of breast cancer drug Herceptin revealed

An outline of a mouse heart
Visualization of the coronary vasculature
patterning of an adult mouse heart.
--Courtesy of Haig Aghajanian, Perelman
School of Medicine at the University of
Pennsylvania and Young Kuk Cho

One of the known side effects of the breast cancer drug trastuzumab (Herceptin) is that it can damage the heart and its ability to pump blood effectively, sometimes resulting in mild heart failure, including shortness of breath and chest pain. Previously, scientists didn't know why this happened.

Now, researchers at the University of Pennsylvania in a preclinical study have discovered that the biological target of trastuzumab is also necessary for normal heart blood vessel development. The finding was published this month in the journal Nature Communications. Approved by the FDA in 1998 as the first targeted cancer therapy, Herceptin is often hailed as the poster child for personalized medicine. It’s most often prescribed to patients with breast cancer caused by a mutation in the HER2 gene. This gene, also known as HER2/neu and ErbB2, is found in excess levels in 20-30% of early-stage breast cancers.

"ErbB2 is a well known target in cancer therapy, but not in vascular biology," first author Haig Aghajanian, a postdoctoral fellow at Penn Medicine, said in a university statement. "Our work identifies a new role for this important protein in blood vessel development and gives us a possible explanation for some of the cardiovascular side effects associated with anti-ErbB2 therapies."

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Using a mouse model, Aghajanian and his colleagues found that growth factor ErbB2 is expressed by vascular endothelial cells, which line the interior surface of blood vessels. In blood vessels, it partners with another protein to form a receptor for semaphorin 3d, a vascular guidance molecule that tells cells where to go during the formation of new blood vessels. When this guidance molecule is depleted, Aghajanian and his team found that the coronary veins form incorrect connections within the developing heart. When ErbB2 was lost from developing heart vessel-lining cells in mice, the researchers noticed a similar effect.

Interestingly, ErbB2 had not previously been shown be present in blood vessels.

The findings shed light on the molecular mechanisms behind the cardiovascular side effects of trastuzumab and could lead to better ways to monitor and detect these unwanted effects before they cause problems for patients. The study results also add to scientists’ understanding of how blood vessels grow and offer another possible target to promote or block the growth of blood vessels to potentially treat diseases that affect these vessels, like ischemia and diabetic retinopathy.

- here’s the study in Nature Communications
- read the Penn statement

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