Neutrophil-mediated tissue remodeling in postpartum breast cancer

点击翻译按钮获取中文摘要

PROJECT SUMMARY Neutrophil extracellular traps (NETs) are meshes of genomic DNA with associated proteases that are released by neutrophils during inflammation. Our previously published data established that NET-associated proteases are capable of triggering quiescent, preneoplastic cells to become proliferative. To do this, NETs remodel the extracellular matrix protein laminin to produce an integrin-activating epitope that triggers proliferation. However, whether NETs activated during physiologic tissue remodeling similarly trigger this switch from quiescence to proliferation is unknown. Mammary gland involution—the process by which the gland returns to its pre- pregnancy state—is characterized by apoptosis of ductal cells and significant extracellular matrix remodeling. This process is strikingly similar to that of wound healing, including an initial influx of neutrophils to the tissue. Mammary gland involution creates a tumor-promotional niche and is suggested to be associated with the development of postpartum breast cancer, which accounts for half of all breast cancer cases in women under 40 years of age. To support further research and the ability to therapeutically target the action of NETs, it is necessary to determine the NET-remodeled laminin epitope and which integrin receptors it may activate. Additionally, the contribution of NETs to the tissue remodeling program and the tumor-promotional environment of the involuting mammary gland is still unknown. Studying NETs in this phase may provide a deeper understanding of mammary gland involution as a whole, as well as identify opportunities for preventative therapies against postpartum breast cancer—a particularly devastating disease due to its poor prognosis, increased risk of metastatic disease, and effect on the mothers of young children. I hypothesize that NET remodeling generates a laminin epitope that activates integrin signaling to stimulate the proliferation of preneoplastic cells during mammary gland involution. This project will establish the laminin epitope and the integrin receptors it activates, which will provide crucial information on how quiescent cells may be triggered to proliferate, and will generate tools to further investigate this pathway. Additionally, this project will help determine the specific role of NETs during involution and if they may be a good target for therapies. This is also an exciting opportunity to utilize intravital imaging to determine how neutrophils may contribute to tissue remodeling during mammary gland involution and how we may pharmacologically target NET remodeling to prevent preneoplastic cell growth in a preclinical model. This proposal will investigate how NETs may promote to malignancy through tissue remodeling in the context of mammary gland involution. Ultimately, the work generated in this proposal will set the stage not only for a deeper understanding of the mechanisms of NETs within malignancies, but also for the development of preventative therapies for postpartum breast cancer.