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"Intrinsic and extrinsic mechanisms of metastatic inhibition by IRF5 in human ductal carcinoma"

Erica Pimenta
MD/Ph.D. Program
B.S. 2009, Rutgers College, Rutgers University

Thesis Advisor: Betsy J. Barnes, PhD
Associate Professor
Department of Molecular Biology and Biochemistry

Thursday, April 24, 2014
11:00 A.M., Cancer Center G Level Conference Room


Staining more than 300 human breast tissue samples demonstrates that over 75% of invasive ductal carcinomas have lost expression of interferon regulatory factor 5 (IRF5). Loss of IRF5 correlates with higher tumor grade, indicating that it may be an important biomarker for disease progression. IRF5 is a transcriptional regulator in immune cells, yet its role in the immune response and other cellular processes in ductal epithelial cells has never been examined. Levels of IRF5 are lowest in human breast cancer cell lines that are most invasive. Re-introduction of IRF5 expression in a xenograft mouse model of breast cancer decreased the number and size of primary tumors as well as completely abrogated tumor spread. The focus of this study is to elucidate the mechanisms by which IRF5 inhibits metastasis.
Through cell-based assays we found that overexpression of IRF5 in MCF-7 and MDA-MB-231 cells inhibits cell movement by over 50%. We characterized the protein domain necessary for this function and found that it is not dependent on DNA binding. This is the first evidence of a non-transcriptional role for IRF5.
Metastatic inhibition by IRF5 may also come from its role as a transcriptional immune regulator. IRF5 positively regulates the expression of several cytokines that are potent activators of an inflammatory response. To gain insight into the cytokines that IRF5 regulates, we isolated MDA-MB-231 cells that stably express IRF5 from 3D acini and performed gene expression analysis. We found that cells expressing IRF5 had significantly elevated levels of immune stimulating genes such as CXCL5, CXCL13, IL-33, and IFNg among many others. In transwell assays using IRF5 positive or negative tumor conditioned media, we found that IRF5 positive media caused increased trafficking of human lymphocytes. These data indicate that signaling from IRF5 positive and negative tumor cells is distinct and that IRF5 may play a role in shaping the tumor-immune microenvironment. We postulate that a loss of IRF5 in breast tumor hinders a favorable immune response and allows cell movement beyond the basement membrane.
Further characterizing how IRF5 shapes the tumor microenvironment is essential for the development of clinically relevant immunotherapy strategies.

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