Master switch may halt aggressive breast cancer

Volume 4, Issue 3, 2015

Summary

Researchers find a new approach to block protein in HER2-positive breast cancer.

Photograph of Ruth Lupu, Ph.D., of Mayo Clinic

Ruth Lupu, Ph.D.

Trastuzumab has been touted as a wonder drug for women with HER2-positive breast cancer, an aggressive form of breast cancer that is fueled by excess production of the HER2 protein. However, not all of these patients respond to trastuzumab, and many who do respond eventually acquire resistance.

A team of researchers led by Mayo Clinic has found a promising way to circumvent this obstacle.

They identified a small site in the HER2 protein that enables it to form a molecular switch that sets off a cascade of events that turn normal cells cancerous. The researchers showed that disrupting this site can stem the growth of breast cancer cells, even more effectively than can drugs currently used in practice.

Their study results were published online April 2015 in the Journal of the National Cancer Institute.

"This study is the first to look at the specific sequences for dimerization of HER2 as a possible anti-cancer target," said the study's senior author, Ruth Lupu, Ph.D., a professor of experimental pathology and laboratory medicine and of biochemistry and molecular biology at Mayo Clinic in Rochester, Minnesota. "This finding could be beneficial not only for breast cancer but also for other cancers with abnormal HER2 levels, such as ovarian, stomach and prostate cancers."

The discovery of HER2 and its role in breast cancer has led to the development of several therapies that specifically target its ability to transform cells. Trastuzumab (Herceptin), pertuzumab (Perjeta) and cetuximab (Erbitux) have together significantly extended the lives of women with HER2-positive breast cancer. But none of the treatments has specifically targeted the ability of HER2 cells to join together or to join with other proteins, an essential first step in tumor growth.

Dr. Lupu hypothesized that HER2 activation occurs through a functional site, a section of protein that is ultimately responsible for forming pairs with itself or other proteins of the same receptor family. If such a site were to exist, then blocking it would deactivate HER2, stopping tumor growth and metastasis. Dr. Lupu and her colleagues studied the protein sequence of HER2 and found a region that appeared to be involved.

They introduced a series of deletions into this region and eventually zeroed in on a section that contained just a short stretch of 16 amino acids, the building blocks of proteins. The researchers showed that unlike the wild-type HER2, a mutant protein that was missing this short sequence could not transform normal cells into cancer.

Most importantly, when they added this mutant protein to HER2-positive breast cancer cells, they showed that it halted the growth of these cells, overcoming the molecular makeup that made them aggressive.

At the same time, they treated HER2-positive cells with the drugs trastuzumab, pertuzumab and cetuximab and found that the HER2-mutant outperformed all three HER2-targeted therapies.

"Our study demonstrates that this protein sequence is a druggable target," Dr. Lupu said. "Targeting this sequence could have a much broader impact than other drugs that are currently available because it does not just disrupt HER2, but it actually gets in the way of HER2's dimerization to itself and other family members. As a result, this approach could block many of the different pathways by which cancer-causing signals get sent into the cell."

Dr. Lupu and her colleagues are continuing studies before clinical testing.