Macrophages promote the progression of premalignant mammary lesions to invasive cancer

// Emily C. Carron 1 , Samuel Homra 1 , Jillian Rosenberg 1 , Seth B. Coffelt 2 , Frances Kittrell 3 , Yiqun Zhang 4 , Chad J. Creighton 4 , Suzanne A. Fuqua 5 , Daniel Medina 3 and Heather L. Machado 1 1 Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, USA 2 CRUK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA 4 Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA 5 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA Correspondence to: Heather L. Machado, email: hmachado@tulane.edu Keywords: inflammation, macrophage, early stage lesion, breast cancer progression, mammary Received: August 15, 2016     Accepted: December 26, 2016     Published: January 31, 2017 ABSTRACT Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention.