US researchers studying breast tumors thought to be HER2-negative, found they contained small groups of aggressive, treatment-resistant HER2-positive breast cancer stem cells (BCSCs).
Jian Jian Li, director of translational research in the Department of Radiation Oncology at the University of California Davis School of Medicine in Sacramento, and colleagues, describe how they uncovered these paradoxical characteristics in the 15 December issue of the journal Clinical Cancer Research.
HER2HER2 is a receptor that is present on the surface of certain cancer cells. Receptors are special proteins that allow ligands, other proteins or compounds, to attach to them (like a lock accepting a unique key). Such attachments trigger particular cell processes, such as growth and repair.
When human epidermal growth factor attaches itself to HER2 receptors on breast cancer cells, it can trigger cell growth and proliferation.
A tumor is said to be HER2-positive when its cancer cells have a lot more HER2 receptors than other cancer cells. Estimates suggest 1 in 5 breast cancers have HER2-positive tumors.
HER2-positive tumors tend to be more aggressive and grow more quickly than other types of breast cancer.
HER2 status is one of the factors that clinicians test for in determining the type of breast cancer. They also test for two other receptors: estrogen receptor (ER) and progesterone receptor (PR).
Whether a tumor has HER2, ER, or PR, or all three, or none, can make a huge difference to its aggressiveness, the patient's overall prognosis and treatment options.
HER2-positive breast cancers are treated with drugs that target the protein, such as Herceptin or Tykerb, with good results.
However, until recently, clinicians would never have considered whether such drugs should also be given to patients with HER2-negative breast cancers.
HER2-Positive BCSCs Isolated from Irradiated, HER2-Negative TumorsLi and colleagues isolated the HER2-positive BCSCs from irradiated, HER2-negative breast tumors.
They also checked the stem cells for CD44 and CD24, cell surface proteins that act as BCSC markers and indicate how aggressive the cancer is.
They found BCSCs that were HER2-positive, CD44-positive, and CD24-negative or -low, were more aggressive and highly resistant to radiotherapy.
But Herceptin and an emerging "gene silencing" treatment called short interfering RNA, appeared significantly to reduce these features.
57.1% of primary tumors and 84.6% of recurrent tumors contained HER2-positive and CD44-positive BCSCs, they found.
"These BSCSs are very resistant to traditional treatments, which can lead patients to relapse," says Li in a statement.
"Despite chemotherapy, radiotherapy or even surgery, the cancer is still recurrent. These findings change our concept of breast cancer because now we know HER2-negative breast cancers can be treated effectively with anti-HER2 treatments," he adds.
How the BCSCs Maintain Resistance to TreatmentThe study also provides new insights into how the BCSCs maintain resistance to cancer treatment.
The researchers found evidence that a complex network of proteins, including HER2 and STAT3 (a transcription activator that controls gene expression), help regulate metastasis or cancer spread, cell death, and other cell processes. The network is what helps the cancer cells survive a whole range of traditional anti-cancer therapies.
The team believes their findings make a significant contribution, both to researchers and clinicians.
"We now have a better understanding of how BCSCs resist radiation and other treatments," explains Li.
Recent studies have shown that patients with HER2-negative breast cancer can benefit from HER2 treatments, but nobody could explain why.
This study provides a detailed reason for why HER2 treatment can benefit patients with HER2-negative breast cancers.
Opens New Diagnostic and Treatment PathwaysThe researchers suggest their findings do more than propose a new treatment route: they also open a new diagnostic pathway for HER2-negative breast cancers.
Markers like CD44 could be used to identify aggressive,HER2-positive BCSCs in cancers that present as HER2-negative. This would allow treatment to be tailored to individual patients.
The study also opens a new treatment route for other cancers, as Li explains:
"This may open the possibility of treating HER2-positive stem cells in bone, lung or brain cancers, which are all difficult to treat in the later stages."
Funds from the National Institutes of Health and a grant from the US Department of Energy Office of Science helped finance the study.