Researchers Find Clues to Resistance in HER2-Positive Breast Cancer

Differences in HER2 homodimers on breast cancer cells may result in functional differences, with possible implications for metastasis and drug resistance, according to the results of a study published in Science Advances.

Using a novel fluorescence-based imaging technique, researchers found that HER2 homodimers-two HER2 transmembrane proteins linked together-form clusters at the plasma membrane of breast cancer cells that likely contribute to the ability of these cells to translocate to other parts of the body.

HER2 plays a role in the progression of some breast cancers and can also influence the aggressiveness of a cancer. In tumors that overexpress HER2, intratumoral heterogeneity of HER2 has been linked to drug resistance and decreased disease-free survival.

To study the distribution of HER2 on breast cancer cells, Diana Peckys, PhD, and Niels de Jonge, PhD, of Saarland University in Saarbrücken Germany, and Ulrike Korf, PhD, of the German Cancer Research Center in Heidelberg, Germany, developed a two-part imaging technique to visualize the distribution pattern of HER2 on breast cancer cells.

The researchers visualized HER2 molecules by first creating affibodies-proteins similar to but smaller than monoclonal antibodies-to bind to HER2. These affibodies were linked to quantum dots, which glow in the presence of light. Cells incubated with the affibodies against HER2 were then visualized with correlative fluorescence microscopy and environmental scanning electron microscopy.

The approach showed two main classes of HER2-expressing breast cancer cells. About 7% of cells within a population had a flat surface membrane and weak HER2 expression. The vast majority of cells had a surface membrane with a ruffled appearance. Some of these ruffled membrane cells had a homogenous distribution of HER2 on the cell surface while others had HER2 clusters at elongated plasma membrane regions at the leading edge of the cell. The number of HER2 molecules found on each of these cells greatly varied.

Because HER2 can be found as a monomer protein or as homodimers or heterodimers, the study authors next assessed whether these forms of HER2 differed depending on their cellular location. It turned out that HER2 homodimers were more likely to be present at the leading edge of ruffled breast cancer cells while cells with equal HER2 distribution had HER2 present in all three states.

The study confirms previously published observations that HER2 is preferentially found on breast cancer cells with a ruffled membrane appearance. The work provides new details on the heterogeneity of HER2 distribution within a population of HER2-positive breast cancer cells.

“Because intratumoral heterogeneity of oncogenic receptors such as HER2 has been linked with the risk of cancer progression, understanding the molecular mechanisms behind the spatial heterogeneity of HER2 and in general of receptor tyrosine kinases might inspire new and more effective therapeutic concepts,” wrote the authors in their discussion.