Breast tumors that are both estrogen-receptor (ER)- and HER2-positive are typically slow-growing, while ER-negative, HER2-positive cancers are more aggressive. Now, researchers at Baylor College of Medicine have discovered a pathway by which ER/HER2-positive breast tumors can transform into more aggressive, ER-negative-like subtypes—a discovery they believe could eventually change the way breast cancer is tracked and treated.
Using a mouse model that allowed them to study breast cancer progression, the Baylor team discovered there are two types of ER-negative tumor cells: The first is fast-growing but not so quick to metastasize, while the second originates from ER-positive cells and is fast both to grow and to metastasize. They published their findings in the Proceedings of the National Academy of Sciences.
The researchers started by setting up mouse models with equal amounts of ER-positive/HER2-positive cells and ER-negative/HER2-positive cells. They watched the cells over time using a red fluorescent protein to track all cells arising from the ER-positive cells. That’s how they discovered that some tumor cells lost their estrogen receptors over time. What’s more, the ER-negative cells that emerged were quick to grow and spread.
They went on to study the DNA of the mammary gland cells in an attempt to discover exactly what was happening to cause some cells to lose their estrogen receptors. The answer? The enzyme MAP kinase was activated differently in the cells, leading to disparities in their aggressiveness.
Aggressive breast cancer is challenging to treat, as patients often become resistant to drugs. Several alternative treatment strategies are being investigated, many of which are aimed at improving responses and avoiding resistance. A team of Italian scientists, for example, reported recently that inhibiting a type of short non-coding RNA could make breast cancer cells 20 times more sensitive to one type of chemotherapy.
Last month, a team led by Purdue University said a novel compound derived from a medicinal shrub could inhibit the protein BRAT1 in cancer cells, stopping the cells from metastasizing and making them more treatable with chemotherapy.
The Baylor researchers believe an improved understanding of how breast cancer cells evolve over time could inspire treatment strategies that change along with them, potentially boosting outcomes. They are now thinking about designing future studies to investigate whether the changes they saw in the mice also occur in people.
“Currently, all ER-/HER2+ breast cancers are treated in the same way and produce diverse responses,” said co-author Jianming Xu, Ph.D., Baylor professor of cell biology, in a statement. “Our findings suggest that different treatments might be in order.”