Data, Algorithms Provide Critical Insight to HER2-Positive Breast Cancer

Studying HER2-positive breast cancer at the cellular level may yield new treatments.

Breast cancer is becoming increasingly prevalent among American women. While effective lifesaving treatments have emerged, breast-cancer-related mortality remains the second leading cause of cancer deaths.

Researchers are now harnessing algorithms and lab experiments to study breast cancer at the cell level to determine how the cells metastasize, according to a study published by Integrative Biology.

Specifically, the authors are looking at the HER2 gene. HER2-positive breast cancer tends to be more aggressive and metastasize faster compared with other subtypes. Overexpression of the HER2 gene is present in 20% of all breast cancers, making targeted treatment approaches valuable.

To determine why these cancers are highly aggressive, the authors analyzed data from a previous study that isolated signaling molecules in a HER2-positive breast cancer cell line and a normal breast cell line, according to the study.

“We use mathematical approaches to find similarities in the data,” said researcher Kristen Naegle, PhD. “For this dataset, we looked at how signaling molecules are most related to each other in the normal cells, compared to how they are related to each other in the HER2-overexpressing cells. We looked for relationships that are drastically different in the 2 cell types to understand how signaling is altered.”

The hope was that the authors would discover distinct differences between the cell lines that could lead to more effective treatments.

“Despite the fact that individual molecules are highly similar to each other across cell types, we found that small changes in signaling dynamics led to very large changes in the relationships uncovered between groups of signaling molecules,” Dr Naegle said.

A significant change they found involves a protein that controls how cells are connected, according to the study.

“One of the things that decreases metastatic behavior is that the cells stick tightly together through cell-cell junctions,” Dr Naegle said. “That told us that if there are signaling alterations happening at the cell junctions, then maybe that’s why these cells are more metastatic.”

The team of researchers tested a hypothesis that interactions within the cell junction protein were changed. They discovered that the interactions between the 2 cell types were extremely different and matched the dynamics of the signaling, according to the study.

“This is exciting, because it’s been proposed that testing for interactions in a cancer biopsy may be a better predictor of how a cancer will respond to a treatment,” Dr Naegle said. “Given that some HER2-positive breast cancer patients don’t respond to HER2 therapy, maybe this protein interaction could help us identify patients who will respond well to therapy and those who will not gain additional benefits.”

The authors conducted further experiments that tested whether cell junctions were changed in the cells with HER2 overexpression. They discovered that the cell junctions in HER2-positive cells tend to break down and become “leaky” in response to the growth factor, according to the study.

The authors believe that these findings may be linked to how HER2-positive cancers spread.

“This study shows that by using a different mathematical interpretation of the data, even a decade after its first publication, we can still find new nuggets of information hidden in these high-throughput, systems-level measurements of early signaling dynamics and identify novel, unknown findings,” Dr Naegle said.

While additional studies are needed to confirm the results, these findings could lead to a novel way to attack HER2-positive breast cancers.

“My lab believes that disease is a context shift, so what we should fundamentally understand is how context shapes cell decisions and then understanding disease becomes relatively trivial,” Dr Naegle concluded. “It’s a bottom-up approach where we look to understand the basic mechanisms of the interactions in the cell to find the outcomes. There still remains a wealth of hypotheses from this analysis that may continue to help us understand how HER2 drives metastasis.”