A significant advancement in breast cancer research has provided a deeper understanding of the mechanisms behind cancer invasion and the development of drug resistance, shedding light on new avenues for treatment. A study conducted by the University of Liverpool, published in Science Advances, reveals how two crucial molecules, HER2 and αVβ6 integrin, work together in HER2-positive breast cancer, one of the most aggressive and difficult-to-treat types of breast cancer. The findings offer valuable insights into why some breast cancers become resistant to treatment and how they continue to spread even after initial therapies.
HER2-positive breast cancer is characterized by the overexpression of the HER2 receptor on the surface of cancer cells. This type of cancer is particularly aggressive and often requires targeted therapies such as trastuzumab (Herceptin), which specifically blocks the HER2 receptor to prevent cancer cell growth. While trastuzumab has been highly effective for many patients, resistance to this treatment can develop, rendering the cancer harder to treat and increasing the risk of metastasis.
The recent study focuses on the interaction between HER2 and αVβ6 integrin, a protein found on the surface of cells. Both molecules have independently been linked to poor cancer outcomes in HER2-positive breast cancer, but this research uncovers a previously unknown mechanism of communication—or “crosstalk”—between them. This interaction is crucial for driving cancer cell invasion, enabling the cancer to spread through tissues, which is a hallmark of advanced disease. The discovery reveals that the crosstalk between HER2 and αVβ6 integrin plays a central role in the progression of breast cancer, especially in the context of drug resistance.
Using advanced proteomic analysis, the research team was able to uncover how the activation of αVβ6 integrin recruits HER2 along with a network of other molecules, including RAB5, RAB7A, and GDI2. These molecules work together to control the movement of HER2 and αVβ6 within the cell and to trigger signals that drive cancer cell invasion. This coordinated molecular network ensures that both HER2 and αVβ6 perform their roles in tumor progression, helping the cancer grow and invade surrounding tissues.
However, the study also highlights a critical aspect of how cancer cells adapt to therapy. In trastuzumab-resistant breast cancer cells, the molecular network involving αVβ6 and HER2 is disrupted. One of the key regulators in this network, GDI2, is lost in resistant cells. The absence of GDI2 causes the breakdown of the αVβ6-HER2 connection, preventing the normal communication between these molecules. As a result, cancer cells adapt and become more invasive by using alternative pathways that bypass the blocked αVβ6-HER2 interaction. This finding is particularly important as it explains why drugs that target HER2 or αVβ6 may become ineffective in resistant cancer cells, allowing the disease to progress.
Furthermore, the study links these molecular interactions to patient outcomes, providing potential clinical applications. Higher levels of GDI2 in tumor cells were associated with better survival rates, suggesting that GDI2 may serve as a potential biomarker for identifying patients with a lower risk of resistance. On the other hand, the expression of αVβ6 was found to predict an increased likelihood of relapse after trastuzumab treatment. This makes αVβ6 a promising target for future therapies designed to overcome resistance and improve patient outcomes.
The lead researcher, Dr. Mark Morgan, emphasized the significance of these findings in understanding how breast cancer invades tissue and how it becomes resistant to targeted treatments. He stated, “The discovery of the αVβ6-HER2 crosstalk mechanism and its disruption in resistant cells opens up new possibilities for therapeutic interventions. By targeting this network, it may be possible to prevent or delay the onset of resistance in HER2-positive breast cancers.”
One promising direction for overcoming resistance involves targeting the RAB5/RAB7A/GDI2 molecular module that facilitates the crosstalk between HER2 and αVβ6. By restoring the normal function of this network, it may be possible to prevent or slow the development of resistance in breast cancer cells. Additionally, monitoring the expression of αVβ6 could help identify patients at higher risk of treatment failure, allowing clinicians to tailor therapies more effectively.
The study also proposes the possibility of developing new drugs that specifically target cells with high αVβ6 levels. These resistant cells, which display elevated αVβ6 expression, could be targeted with therapies designed to either deliver a lethal “warhead” to the cancer cells or reprogram them to be recognized and attacked by the patient’s immune system. This approach would be aimed at overcoming the limitations of current drugs like trastuzumab, which lose effectiveness in the face of resistance.
Dr. Simon Vincent, Director of Research, Support, and Influencing at Breast Cancer Now, praised the study for its potential to improve treatment strategies. “This promising study helps us understand not only how αVβ6 and HER2 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,” he said. He added that drug resistance remains one of the most significant challenges in breast cancer treatment, particularly for HER2-positive cases where trastuzumab resistance is common. Understanding the mechanisms behind resistance will allow for the development of more effective treatments and personalized therapies that can help prevent relapse and improve survival outcomes.
The discovery of this molecular interaction and its impact on resistance provides hope for more targeted and individualized therapies in the future. As Dr. Vincent noted, “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 ultimately lead to new treatments that prevent drug resistance from developing, reducing the number of patients who experience treatment failure and improving survival rates for those with HER2-positive breast cancer.
This research is a crucial step forward in the ongoing battle against breast cancer, especially in addressing the challenge of drug resistance. As the study demonstrates, cancer cells can hijack normal cellular processes to spread and evade therapies, making it essential to develop new treatment strategies that target these adaptive mechanisms. By focusing on the molecular networks that drive resistance, scientists can begin to uncover new ways to prevent the progression of HER2-positive breast cancer, offering hope to patients and advancing the field of cancer research.
Source: University of Liverpool