Women with triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, have the shortest survival times and the highest rate of relapse. These patients have no currently available forms of targeted therapy and most (~77%) succumb to metastases within 5 years. However, the nature of how metastasis relies on signaling from the tumor microenvironment is not well understood. Macrophages have also been linked to human breast cancer invasion and metastasis as well as drug resistance, and recently have been implicated in TNBC. M1-like pro-inflammatory macrophages are thought suppress tumor growth and metastasis, whereas the tumor-associated macrophages (TAMs) are characterized as M2-like pro-metastatic macrophages. However, recent proteomic and RNA studies indicate that macrophage populations are composed of more phenotypic subtypes than previously recognized. Thus, the phenotype of TNBC TAMs and the mechanisms by which they interact with TNBCs are not well understood and require further characterization. In recent studies I have been testing the hypothesis that TNBC recruits a unique subtype of TAMs via CCL5 that drives invasion and metastasis. Using genetically matched metastatic and non-metastatic TNBC tumors that differ only by expression of the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP), I show that RKIP alters not only the number of recruited TAMs but also their phenotype. I further demonstrate that CCL5 expressed by metastatic tumors recruits TAMs that secrete pro-metastatic factors, promote invasion of TNBC cells, are highly expressed in human TNBC patients, and contribute to a prognostic signature for patient survival. Taken together, these findings suggest that TNBC recruited TAMs are both phenotypically and functionally distinct from other TAMs, and M1 or M2 macrophages. I now propose to test the hypothesis that these TAMs can be distinguished by unique surface receptors that regulate expression and secretion of pro-metastatic factors. I further propose that TAMs recruited by CCL5 to metastatic TNBCs drive metastasis through expression of GRN along with other associated factors. Specifically, I will: 1) Characterize the phenotype of pro-metastatic TAMs in TNBC; and 2) Determine the functional role of TAMs & TAM secreted factors in TNBC metastasis. This study is innovative because it seeks to understand the phenotype of a novel TAM subtype identified in TNBC, as well as the in vivo mechanism of TAM driven invasion in TNBC. Together, these results could generate new diagnostic markers and prognostic signatures as well as identify potential therapeutic targets to deplete or reprogram pro-metastatic TAMs in TNBC patients. This work should also lead to a better understanding of the role of TAMs in the poor outcomes of TNBC patients.

Public Health Relevance

15-20 percent of women diagnosed with breast cancer have triple-negative breast cancer (TNBC), which has no forms of targeted therapy. This study aims to characterize a unique subtype of pro-metastatic tumor associated macrophages (TAMs) in TNBC. Understanding these TAMs and the mechanism by which they drive metastasis may elucidate risk factors and/or biomarkers as well as potential therapies for this aggressive form of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Schmidt, Michael K
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Frankenberger, Casey; Rabe, Daniel; Bainer, Russell et al. (2015) Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages. Cancer Res 75:4063-73