Tumor necrosis factor-alpha-converting enzyme activities and tumor-associated macrophages in breast cancer Stephen L. Rego • Rachel S. Helms • Didier Dre ´au Published online: 27 September 2013 Ó Springer Science+Business Media New York 2013 Abstract The role of the tumor microenvironment espe- cially of tumor-associated macrophages (TAMs) in the progression and metastatic spread of breast cancer is well established. TAMs have primarily a M2 (wound-healing) phenotype with minimal cytotoxic activities. The mecha- nisms by which tumor cells influence TAMs to display a pro-tumor phenotype are still debated although the key roles of immunomodulatory cytokines released by tumor cells, including colony-stimulating factor 1, tumor necrosis factor (TNF) and soluble TNF receptors 1/2, soluble vas- cular cell adhesion molecule 1, soluble interleukin 6 receptor and amphiregulin, have been demonstrated. Importantly, these factors are released through ectodomain shedding by the activities of the tumor necrosis factor- alpha-converting enzyme (TACE/ADAM17). The role of TACE activation leading to autocrine effects on tumor progression has been extensively studied. In contrast, limited information is available on the role of tumor cell TACE activities on TAMs in breast cancer. TACE inhib- itors, currently in clinical trials, will certainly affect TAMs and subsequently treatment outcomes based on the sub- strates it releases. Furthermore, whether targeting a subset of the molecules shed by TACE, specifically those leading to TAMs with altered functions and phenotype, holds greater therapeutic promises than past clinical trials of TACE antagonists’ remains to be determined. Here, the potential roles of TACE ectodomain shedding in the breast tumor microenvironment are reviewed with a focus on the release of tumor-derived immunomodulatory factors shed by TACE that directs TAM phenotypes and functions. Keywords Breast cancer Á Macrophages Á Ectodomain shedding Á Tumor necrosis factor-alpha-converting enzyme Introduction In addition to their intrinsic properties, breast tumor cell growth and ability to form metastases rely heavily on interactions with stromal cells in the breast tumor micro- environment [1, 2]. Indeed, within the breast tumor microenvironment, structural proteins from the extracellu- lar matrix (ECM) and both soluble and insoluble factors generated by tumor cells and stroma cells including immune cells, fibroblasts, endothelial cells and adipocytes modulate cancer progression. Although each of these stroma cells influences breast cancer progression, tumor- associated macrophages (TAMs) in particular have been associated with worsened clinical outcome in breast cancer patients [3, 4]. Macrophages located in and around the tumor, i.e., the TAMs have both anti- and pro-tumor activities [5–9] that have been detailed thoroughly in breast cancer [3, 6, 10– 15]. TAMs display diverse functions and lie on a pheno- type continuum from M1 macrophages with antitumor properties (classically activated) to M2 macrophages with pro-tumor properties (alternatively activated) [16]. It should be emphasized that this classification system was developed to highlight the markers and functions of M1 and M2 macrophages in different contexts and may not precisely represent the antitumor and pro-tumor TAMs, respectively. Indeed, other distinct populations of mono- cyte-derived cells isolated within the breast tumor S. L. Rego Á R. S. Helms Á D. Dre ´au (&) Cell and Molecular Division, Department of Biological Sciences, University of North Carolina, Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA e-mail: ddreau@uncc.edu 123 Immunol Res (2014) 58:87–100 DOI 10.1007/s12026-013-8434-7