The Role of NF-kappaB in Stromal Macrophage Influence on Breast Cancer Tumorigene

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DESCRIPTION (provided by applicant): Macrophages are essential components of the immune system and are recruited from the blood stream to tumors where they contribute to the tumor stroma and promote oncogenic phenotypes. In certain cancers, like those of the breast, tumor-associated macrophages (TAMs) comprise a significant portion of total tumor mass, which correlates with poor patient prognosis. TAMs are often activated by cancer cells to an M2 immunosuppressive phenotype, which results in the production of anti-inflammatory factors, promotion of angiogenesis and tissue remodeling activity, and makes them poor antigen presenters. It is still unclear how tumors alternatively activate stromal macrophages and how these different phenotypes promote tumorigenesis, but the NF-:B transcription factor pathway has been implicated. In response to macrophage release of growth factors/cytokines, the NF-:B pathway might be activated in cancer cells to promote epithelial-mesenchymal transition (EMT) in tumor cells, which can lead to tumor initiating cell (TIC) generation and metastasis. Because the NF-:B pathway has the potential to be targeted therapeutically, understanding how NF-:B activation influences TAM phenotype is important. Our hypothesis is that tumors activate stromal macrophages via NF-:B, typically to an M2 immunosuppressive phenotype, which reciprocally increases NF-:B activation in the tumor cells. This influences EMT, and ultimately, increases generation of TICs to enhance tumorigenesis. Disruption of this NF-:B feedback loop between cancer cells and macrophages may lead to decreased EMT, fewer TICs, and therefore, decreased tumor size and metastases, and enhanced chemotherapy sensitivity. To test our hypothesis, we will analyze three specific aims addressing the following questions: (i) Does breast cancer activation of macrophages function to enhance EMT and breast cancer phenotypes? (ii) Is the NF-:B pathway involved in stromal macrophage promotion of breast cancer tumorigenesis? (iii) Does NF-:B inhibition, potentially by affecting macrophages, decrease tumorigenesis in basal-like and human claudin-low breast tumor models? To answer these questions we will utilize cell-based assays and mouse models of basal-like and claudin-low breast cancer and mouse models that have NF-:B and IKK knocked out in myeloid cells. Importantly, these models will allow us to determine if pharmacological inhibitors against the NF-:B pathway result in decreased tumorigenesis, potentially through targeting macrophages. This application proposes the first in-depth study of tumor-associated macrophages and breast cancer using in vivo models. This project is directly relevant to public health because it will determine pathways in tumor-associated macrophages that lead to dysregulated immunological and tumor promoting activity. Inhibiting the cancer promoting activity of tumor associated macrophages could have major therapeutic benefits for chemoresistant cancers, including breast cancer.