Targeting pro-metastatic neutrophils to inhibit breast cancer metastasis

Breast cancer is the most frequent cancer among women in the United States with over 230,000 new cases and 40,000 deaths every year. Among all the types of breast cancers, triple-negative breast cancers, which are not stimulated to grow from exposure to hormones estrogen and progesterone and protein Her2, are more aggressive than other breast cancers and have fewer treatment options. Metastases, a stage of breast cancer where the tumor cells have released from the breast and travel to other organs in the body, are the cause of 90% of breast cancer deaths. Therefore, it is critical and urgent to find the effective treatment to inhibit metastasis. In our previous study, we found that tumor cells frequently interact with neutrophils which is the most abundant immune cells in our blood, during their travel in the blood to the distant organs. However, the consequence of their interaction is unknown. Based on recent studies demonstrating that neutrophils can promote metastasis, we will determine whether neutrophils promote metastasis by interacting with tumor cells in the blood, and identify the molecules mediating their interaction in both triple negative breast cancer patients and a specific mouse model that can grow human breast cancers. After their identification, we will determine whether these molecules can be used to predict metastasis in the patients. Since anti-asthma drug Zileuton has been found can prevent neutrophils to promote metastasis by inhibiting Alox5 enzyme, we will determine whether another two natural products Hyperforin and Boswellia which have the same function as Zileuton to inhibit Alox5 enzyme, can also inhibit metastasis-promoting function of neutrophils, and the mechanisms why inhibition of this enzyme can block metastasis. At last, previous studies indicate that neutrophils have the ability to inhibit functions of T cells by expressing PD-L1 protein on their surface. Since T cells play the key role in our immune system to kill cancer cells before they form the cancer in our body, this is another explanation for metastasis-promoting function of neutrophils. The immunotherapy known as anti-PD-1 treatment has developed and generated great excitement for its ability to help T cell recognize and attack tumor cells. We will explore whether combine the PD-1 treatment (to help T cell recognize tumor cells) with Alox5 inhibitors (to prevent neutrophils from inhibiting T cells function) can enhance their efficacy to block metastasis. We expect to develop more effective and less toxic treatments for metastatic breast cancer.