A significant advance in breast cancer research has uncovered a key mechanism driving cancer invasion and drug resistance. A University of Liverpool study reveals how two critical molecules present in "HER2-positive" breast cancer—one of the most aggressive forms—influence breast cancer survival and its spread. The findings are published in the journal Science 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 newly 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, offering valuable insights into why some breast cancers become harder to treat.

The research team used advanced proteomic analysis to uncover that when α_Vβ₆ integrin is activated, it recruits HER2 along with a network of molecules known as RAB5, RAB7A and GDI2. This network facilitates direct communication between α_Vβ₆ and HER2, controls how they move within cells and triggers signals that drive cancer.

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

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

Dr. Mark Morgan, the study's lead researcher and Senior Lecturer in Molecular & Clinical Cancer Medicine said, "These findings are pivotal to understanding how breast cancer invades tissue, but also how it becomes resistant to targeted treatments. The discovery of this α_Vβ₆-HER2 crosstalk mechanism, and its disruption in resistant cells, opens up 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. Moreover, monitoring α_Vβ₆ expression in patients could help predict treatment outcomes and guide personalised 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 counteract drug resistance.

Dr. Morgan adds, "The study also found invasion of trastuzumab resistant cells is no-longer stopped by reagents that block α_Vβ₆ function. However, these resistant cells have very high levels α_Vβ₆ on their surface. So, we now want to explore developing new drugs that specifically target cells with high α_Vβ₆ levels and either deliver a lethal warhead, or re-program them to be targeted by the patient's own immune system."

Dr. Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, concluded, "This promising study helps us understand not only how α_Vβ₆ and HER-2 proteins work together to drive the growth of breast cancer but could also enable us to identify why some patients' breast cancers become resistant to treatments.

"Drug resistance remains a huge 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 vital we understand how resistance arises so that when it does, patients are not limited to a single line of defense. This research could help us identify which patients are likely to be resistant as well as lead to new therapies for HER2-positive breast tumors, which are more targeted, and could ultimately stop people dying from this devastating disease."