A major breakthrough in breast cancer research has uncovered the key mechanism that drives malignant invasion and medication resistance.
A University of Liverpool study demonstrates how two crucial molecules found in ‘HER2-positive’ breast cancer, one of the most aggressive types, affect breast cancer survival and spread.
These proteins, HER2 and aVb6 integrin, are already known to individually predict cancer outcomes, but they now function together via a newly discovered ‘crosstalk’ process that promotes cancer cell invasion.
Importantly, this pathway is broken in breast cancer cells resistant to trastuzumab, a commonly used treatment for HER2-positive breast cancer, providing vital insights into why some breast cancers become more difficult to treat.
The researchers employed advanced proteomic analysis to discover that when the aVb6 integrin is activated, it recruits HER2 as well as a network of molecules known as RAB5, RAB7A, and GDI2. This network allows for direct contact between aVb6 and HER2, regulates how they travel inside cells, and activates signals that cause cancer.
However, in trastuzumab-resistant breast cancer cells, this sophisticated network fails. The network’s primary regulator, GDI2, is lost, disrupting the aVb6-HER2 connection. As a result, the cancer adapts and becomes more invasive via other pathways, making medications that block aVb6 or HER2 no longer effective in preventing cancer invasion. This demonstrates a key shift in how cancer cells adapt to combat the impacts of targeted therapy.
The study’s findings also establish a link between molecular interactions and patient outcomes. Higher levels of GDI2 are linked to better survival rates, but aVb6 expression indicates a higher risk of relapse following trastuzumab treatment. This makes aVb6 a promising biomarker for identifying individuals at increased risk of treatment failure, as well as a possible target for resistance-overcoming medicines.
Dr. Mark Morgan, the study’s lead researcher and Senior Lecturer in Molecular & Clinical Cancer Medicine, stated, “These findings are critical to understanding how breast cancer invades tissue as well as how it grows resistant to targeted treatments. The identification of this aVb6-HER2 crosstalk pathway, as well as its blockage in resistant cells, provides novel paths for therapeutic intervention.”
Targeting the RAB5/RAB7A/GDI2 module or restoring its normal function may be able to prevent or delay the emergence of resistance in HER2-positive breast tumors. Furthermore, tracking aVb6 expression in patients should aid in predicting therapy outcomes and guiding personalized medicines.
The discovery is an important step toward understanding how HER2-positive breast cancer cells use normal biological processes to spread and elude treatments. The study not only sheds light on the biology of cancer progression, but it also offers a potential path for developing new medication resistance-fighting tactics.
Dr. Morgan stated, “The study also discovered that chemicals that disrupt aVb6 function no longer limit the invasion of trastuzumab-resistant cells. However, these resistant cells have extremely high quantities of aVb6 on their surfaces. So, we want to look at developing novel drugs that precisely target cells with high aVb6 levels and either deliver a lethal warhead or re-program them to be targeted by the patient’s own immune system.”
-NSH Digidesk
