Novel chemokine in the regulation of breast cancer metastasis

Project Summary Our long-term goal is to understand the immunobiology of cancer and identify the molecular drivers that promote the metastatic progression of cancer. We discovered that a potent chemokine, CCL24, is expressed explicitly by aggressive estrogen receptor-negative breast cancer cells. Our preliminary data

validated that the expression of CCL24 is significantly higher in breast cancer and that high CCL24 mRNA levels in aggressive breast cancer is associated with poor prognosis. Permutation studies revealed that siRNA-mediated knockdown of CCL24 in overexpressing breast cancer cells promoted mesenchymal-to-epithelial transition (MET). CCL24 may promote cancer cell EMT and metastasis as a

known chemoattractant for immunosuppressor cells to further suppress antitumor immunity. Therefore, we hypothesize that the chemokine ligand CCL24 drives invasive features of breast cancer cells leading to metastasis. Our specific aims are: 1) to determine the clinical significance of CCL24 in breast cancer and its induction of EMT and unfavorable clinical outcomes; and 2) to determine the

oncogenic function of CCL24 and therapeutic targeting of CCL24 in breast cancer. In parallel, we will determine if CCL24 contributes to breast cancer metastasis by promoting the infiltration of immunosuppressive cells at the breast tumor site. This innovative concept explores previously unknown roles for CCL24 as a driver of metastatic progression of aggressive breast cancer. We expect to provide

preclinical proof-of-concept of oncogenic function and therapeutic targeting of CCL24 in breast cancer.