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A remarkable development in breast cancer research has revealed a fundamental mechanism behind increased cancer invasiveness and drug resistance.
A study from the University of Liverpool reveals how two key molecules present in ‘HER2-positive’ breast cancer – one of the most aggressive forms – affect breast cancer survival and its spread.
These proteins, HER2 and aVb6 integrin, are already known to independently predict cancer outcomes, but have now been found to work together through a newly discovered ‘crosstalk’ mechanism that is responsible for cancer cell Inspires attack.
Importantly, this mechanism is disrupted in breast cancer cells resistant to trastuzumab, a common treatment for HER2-positive breast cancer, providing valuable insight into why some breast cancers are difficult to treat. It becomes difficult.
The research team used advanced proteomic analysis to discover that when the aVb6 integrin is activated, it recruits HER2 along with a network of molecules called RAB5, RAB7A, and GDI2. This network facilitates direct communication between aVb6 and HER2, controlling how they move within cells and triggering cancer-promoting signals.
However, in trastuzumab-resistant breast cancer cells, this complex network breaks down. A key regulator in the network, GDI2, has been lost, disrupting the aVb6-HER2 connection. As a result, cancer adapts and becomes more aggressive through alternative pathways, meaning that drugs designed to block aVb6 or HER2 no longer prevent cancer invasion. This highlights an important change in how tumor cells adapt to overcome the effects of targeted therapy.
The study findings also link these molecular interactions to patient outcomes. Higher levels of GDI2 are associated with better survival rates, whereas aVb6 expression predicts an increased likelihood of recurrence after trastuzumab treatment. This makes aVb6 a promising biomarker to identify patients at high risk of treatment failure and a potential target for therapies to overcome resistance.
Dr Mark Morgan, lead researcher on the study and senior lecturer in molecular and clinical cancer medicine, said: “These findings are important for understanding not only how breast cancer invades tissue, but also how it responds to targeted therapies. “The discovery of the mechanism of this aVb6-HER2 crosstalk, and its disruption in resistant cells, opens new avenues for therapeutic intervention.”
By targeting the RAB5/RAB7A/GDI2 module or restoring its normal function, it may be possible to prevent or delay the onset of resistance in HER2-positive breast cancer. Furthermore, monitoring aVb6 expression in patients may help predict treatment outcomes and guide personalized therapies.
This study represents an important step in understanding how HER2-positive breast cancer cells hijack normal cellular processes to spread and evade treatments. This research not only sheds light on the biology of cancer progression, but also provides a potential roadmap for developing new strategies to counteract drug resistance.
“The study also found that invasion of trastuzumab-resistant cells was no longer prevented by reagents that blocked AVB6 function,” Dr. Morgan said. However, these resistant cells have very high levels of aVb6 on their surface. Therefore, we now want to explore developing new drugs that specifically target cells with high AVB6 levels and either provide a lethal warhead, or allow them to be targeted by the patient’s own immune system. Program from.
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