Polysialic Acid as a Mediator of Breast Cancer Progression and a Potential Biomarker for Risk Stratification

Breast cancer is the leading cause of cancer-related deaths in women worldwide. In the United States alone, it is estimated that over 230,000 women will be diagnosed with breast cancer and over 40,000 women will die from the disease this year. Metastasis, which is the spread of cancer cells from a primary tumor to other areas in the body, remains the main cause of patient-related death due to organ damage caused by the growing metastases. Awareness of the clinical importance of metastasis and our basic scientific understanding of the metastatic process has improved substantially over the past few decades. However, many aspects of metastasis are still not well defined, and our ability to identify patients at high risk for cancer recurrence is limited. Consequently, we treat all patients with toxic chemotherapies, even those with non-metastatic cancer, so that we can minimize the number of fatalities. A test that can discriminate between patients with metastatic and indolent (non-aggressive) disease is greatly needed.

We have identified a sugar on the surface of aggressive breast cancer cells, called polysialic acid (polySia). In healthy humans, polySia acts like a non-stick coating and allows cells to move around the body. This is important for cells of the immune system because they need to migrate towards the site of an infection. However, it is equally important that cells in tissues such as breast, lung, and liver, do not contain polySia and remain attached to adjacent cells. Because we have observed polySia on aggressive breast cancer cells, we think that it may be changing their attachments to adjoining cells and causing them to metastasize. Typically, the only way to determine whether a tumor has polySia would be to perform a biopsy to look at the tissue directly. However, we also discovered that polySia can be found on small tumor cell fragments, called microparticles, in the bloodstream. The only way to analyze these microparticles in detail is using a high-tech instrument called a nanoscale flow cytometer. When we used this to look at blood samples from breast cancer patients, we found a significant link between high levels of polySia microparticles and risk of breast cancer recurrence. Our initial data have led us to the hypothesis that investigation of the role of polySia in metastasis will uncover potential targets for treatment of aggressive breast cancer. Additionally, we may be able to use the presence of polySia in the blood to determine the aggressiveness of a patient's cancer. We have three aims: to determine where and when polySia appears on cancer cells, to determine how polySia contributes to metastasis, and to perform a study that will show how accurate the presence of polySia in the bloodstream is at predicting risk of metastatic recurrence in patients. This will help us understand how breast cancer cells metastasize causing life-threatening metastases and allow us to distinguish aggressive and indolent disease. By understanding the molecule that provides cells with their non-stick coating, we hope to find new ways to prevent this coat from forming. This would significantly reduce metastasis and subsequent mortality in all patients with aggressive disease. As with any new target, development and testing, including clinical trials, will take upwards of 15 years. However, if we find a target for which there is already an approved compound in the Food and Drug Administration database, the time to clinical use could be as little as 10 years. Fortunately, if our study supports the detection of polySia in the bloodstream, the time for development of a blood test would be significantly shorter. If we can also link high levels of polySia with breast tumor tissue, it may be possible to use it in the clinic alongside currently used markers, which means that we could have a test in clinical use in 5 years.

Our research will not end the genesis of breast cancer, but it will make powerful strides towards ending metastasis, the most significant cause of breast cancer-associated mortality. It will also result in the identification of people at very low risk for metastatic disease, allowing for them to bypass the harsh effect toxic chemotherapy treatments.