Researchers discover “crosstalk” mechanism in two key breast cancer molecules

A significant advance in breast cancer research has uncovered a key mechanism behind cancer invasion and drug resistance. A University of Liverpool study reveals how two key molecules found in HER2-positive breast cancer – one of the most aggressive forms – influence breast cancer survival and spread. The results are published in the journal Scientific advances.

These proteins, HER2 and α_Vβ₆ integrin, are already known to independently predict cancer outcomes, but have now been found to work together through a recently discovered “crosstalk” mechanism that drives cancer cell invasion. 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 become harder to treat. to treat.

The research team used advanced proteomic analysis to discover that when α_Vβ₆ the integrin is activated, it recruits HER2 as well as a network of molecules known as RAB5, RAB7A and GDI2. This network facilitates direct communication between α_Vβ₆ and HER2, control their movement into cells and trigger cancer-causing signals.

However, in trastuzumab-resistant breast cancer cells, this complex network breaks down. A key network regulator, GDI2, is lost, leading to disruption of α_Vβ₆-HER2 connection. As a result, cancer adapts and becomes more invasive through alternative pathways, i.e., drugs designed to block α._Vβ₆ or HER2 no longer prevent cancer invasion. This highlights a crucial change in how tumor cells adapt to overcome the effects of targeted therapy.

The study results also link these molecular interactions to patient outcomes. Higher levels of GDI2 are associated with better survival rates, while α_Vβ₆ expression predicts increased likelihood of relapse following trastuzumab treatment. This makes α_Vβ₆ a promising biomarker for identifying patients at higher risk of treatment failure and a potential target for therapies aimed at overcoming resistance.

Dr Mark Morgan, principal investigator of the study and senior lecturer in molecular and clinical cancer medicine, said: “These findings are essential to understanding how breast cancer invades tissue, but also how it becomes resistant to treatments. targeted._Vβ₆The HER2 crosstalk mechanism and its disruption in resistant cells open new avenues for therapeutic interventions. »

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 cancers. Furthermore, monitoring of α_Vβ₆ expression in patients could help predict treatment outcomes and guide personalized therapies.

The study represents a crucial step in understanding how HER2-positive breast cancer cells hijack normal cellular processes to spread and evade therapies. The research not only sheds light on the biology of cancer progression, but also provides a potential roadmap for developing new strategies to thwart drug resistance.

Dr. Morgan adds: “The study also revealed that invasion of trastuzumab-resistant cells is no longer stopped by α-blocking reagents._Vβ₆ function. However, these resistant cells have very high α levels._Vβ₆ on their surface. We therefore now wish to explore the development of new drugs specifically targeting high α cells._Vβ₆ levels and either launch a lethal warhead or reprogram them to be targeted by the patient’s own immune system.

Dr Simon Vincent, Director of Research, Support and Influence at Breast Cancer Now, concluded: “This promising study helps us understand not only how α_Vβ₆ and HER-2 proteins work together to stimulate breast cancer growth, but could also help us identify why some patients’ breast cancers become resistant to treatments.

“Drug resistance remains a major obstacle in the treatment of breast cancer and, unfortunately, resistance to the standard treatment for HER-2 positive breast cancer – Herceptin (trastuzumab) – is common.

“It is essential that we understand how resistance arises so that when it does occur, patients are not limited to a single line of defense. This research could help us identify patients who may be resistant and lead to new treatments for HER2-positive patients. breast tumors, which are more targeted, and which could ultimately prevent people from dying from this devastating disease. »