Immunohistochemical detection of HER2 cancer biomarker with IgY antibody and quantum dots is demonstrated in these samples of breast cancer cells from a patient with normal HER2 expression (top) and one with over production (bottom). Cell nuclei are stained blue, quantum dots responding to the HER2 protein light up in bright red at the cell membranes. Treatment with trastuzumab could only be effective for the latter patient.
Generations of mothers have served up chicken soup to remedy the common cold, but now the therapeutic fowl may find use in diagnosis as well. Researchers at the National Institute of Standards and Technology (NIST), the National Cancer Institute (NCI) and the scientific research firm SAIC recently showed how chicken antibodies may one day improve the detection of an aggressive form of breast cancer.
HER2 is one of a family of genes that help regulate the growth and proliferation of human cells. Normal cells have two copies of HER2, but about 20 to 25 percent of breast cancers have multiple copies of the gene, resulting in the overproduction of a HER2-encoded protein (called HER2) that stimulates tumors to be particularly fast growing and difficult to treat in a subset of breast cancer patients.
Patients with that form of breast cancer—about 40,000 women in the United States annually—can be treated with a monoclonal antibody called trastuzumab that targets and inhibits the growth of tumor cells with higher-than-normal levels of the HER2 protein. But because the treatment can have adverse side effects, it's important to screen for those patients who would benefit from it by testing them for one or both of the two relevant biomarkers: the amplified HER2 gene or its overexpressed HER2 protein. Unfortunately, the existing tests for these biomarkers can yield a significant number of false positives—as many as 23 percent of patients in one 2006 clinical study—resulting in some women getting a somewhat risky and expensive treatment that can't help them.
In a paper in the International Journal of Cancer,* the NIST-NCI-SAIC research team found that chicken immunoglobulin Y (IgY) antibody created against the HER2 protein could be tagged with quantum dots (tiny, intense and tunable sources of colorful light) to more reliably detect the HER2 biomarker than the existing diagnostic tests using mammalian antibodies tagged with conventional fluorescent dyes. Overall, the improvement in sensitivity to the HER2 biomarker was about 40-50 percent.
The increased sensitivity of the HER2 quantum dot-based quantitative bioimaging system stems from the broad genetic differences between avian and human species. The chicken IgY antibody to HER2 reacts strongly with the target protein while ignoring other human proteins that can interfere with current diagnostic tests.
Other advantages of the novel NIST-NCI-SAIC system include faster and larger-scale production of the antibodies and a more reliable quantitative measure of HER2 biomarker level, in part because the quantum dot tags will stay bright and detectable while fluorescent dyes fade over time.
The research was funded under an interagency agreement between NIST and NCI. NIST also is funding the development of a standard reference material to support HER2 testing.
* Y. Xiao, X. Gao, G. Gannot, M.R. Emmert-Buck, S. Srivastava, P.D. Wagner, M.A.Amos and P.E. Barker. Quantitation of HER2 and telomerase biomarkers in solid tumors with IgY antibodies and nanocrystal detection. International Journal of Cancer, posted online Jan. 23, 2008.