Potential cause found for deadly relapse of basal-like breast cancer

Researchers have discovered why some of the most aggressive and fatal breast cancer cells are resistant to chemotherapy, and they are developing ways to overcome this resistance. The protein Engrailed 1 is overexpressed in basal-like carcinomas, and a chain of amino acids has been designed to shut down the protein and kill basal-like tumors in the lab.

“Patients with basal-like breast cancer tend to initially respond well to chemotherapy, but it's common for patients to relapse even more aggressively,” said Adriana S. Beltran, PhD, of the University of North Carolina at Chapel Hill, and lead author of the study results published in Oncogene (2013; doi:10.1038/onc.2013.422). “We believe that relapse is caused by a small number of cancer cells that have stem cell properties that allow them to survive chemotherapy. In these cells, we've identified the overexpression of Engrailed 1.”

Beltran and her colleagues discovered that Engrailed 1 is not involved in the rapid proliferation of cells that cause tumor growth, nor is Engrailed 1 present in luminal tumors—the most common form of breast cancer. The culprit protein only appears in basal-like breast cancer.

In fact, Engrailed 1 is normally confined to the brain, where it protects neurons from cell death and helps maintain their normal activity. The absence of the protein in the brain has been linked to the onset of Parkinson's disease, although there is no known function of Engrailed 1 within breast tissue.

“We think that Engrailed 1 confers protective features to breast cancer cells, similar to the features observed in long-lived neurons,” Beltran said. “This may explain why these cells survive and become resistant to chemotherapy in our experiments.”

The researchers found Engrailed 1 through a series of experiments designed to find genes that are highly expressed in basal-like cells but not in luminal breast cancers. They discovered that Engrailed 1 was most highly expressed in cell lines isolated from inflammatory breast cancer. They also determined that Engrailed 1 was associated with the gene, EPRS, which expresses an enzyme that controls messenger RNA and protein synthesis, particularly in proteins involved with inflammation.

“Inflammation is associated with cancer development,” Beltran said. “It's interesting to us that Engrailed 1, alone, is able to control inflammatory responses that may promote more aggressive forms of cancer.”

The researchers might have found a way to stop Engrailed 1. After studying how Engrailed 1 binds to DNA and other proteins, they created a synthetic peptide—a chain of amino acids—that can stifle the binding power of Engrailed 1. Beltran and her colleagues used this peptide to disrupt Engrailed 1 from binding to its protein partners and DNA in cell lines, although this has not yet been demonstrated on animal or human models.

“Cancer cells need Engrailed 1 to live,” Beltran said. “The peptide abolishes all interactions of Engrailed 1, and as a consequence, Engrailed 1 cannot perform its functions, causing rapid cell death of the cancer cell.”

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