Therapies targeting ErbB2 (HER2), such as trastuzumab (Herceptin), are often associated with cardiovascular side effects, and researchers are beginning to understand why. ErbB2, an epidermal growth factor receptor known to enhance growth of cancer cells, was recently found to also be expressed by vascular endothelial cells that contributes to heart blood vessel development. This discovery is an example of how tissue growth and blood vessel patterning are integrated at the molecular level.1

Researchers at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, found that ErbB2 partners with neuropilin 1 to form a receptor for semaphorin 3d, a vascular guidance molecule. Guidance molecules instruct cell migration, such as when new blood vessels are forming.

“ErbB2 is a well-known target in cancer therapy, but not in vascular biology,” explained Haig Aghajanian, PhD, a postdoctoral fellow at the University of Pennsylvania, and first author on the study. “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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The loss of semaphorin 3d was found to lead to improper connections of the coronary veins forming within the developing heart. A similar effect was also seen when developing heart-vessel lining cells lost ErbB2, providing a genetic link between the pathways.

The emergence of ErbB2 in the search for semaphorin 3d molecular partners was a surprise finding as the association between semaphorin guidance molecules and ErbB receptors was not known.

Aghajanian’s team is continuing their research into ErbB2-targeted therapy and its link to adverse cardiovascular effects. A better understanding of how these adverse effects develop could lead to more effective monitoring and early detection.


1. Aghajanian H, Cho YK, Manderfield LJ, et al. Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor. Nat Commun. 2016 Jun 30. doi: 10.1038/ncomms12038. [Epub ahead of print]