Abstract B64: Macrophage-specific deletion of STAT5 disrupts normal mammary gland development and accelerates mammary tumorigenesis

Fibroblast growth factor receptor 1 (FGFR1) is amplified in 10% of human breast cancers and the ligands for FGFR1 are overexpressed in 60% of triple negative breast cancers. Additionally, amplification of the FGFR1 locus can confer resistance to endocrine-based therapies in patients with estrogen receptor (ER) positive tumors. Previous studies using a mouse model of FGFR1-induced mammary tumorigenesis demonstrated that FGFR1 activation in mammary epithelial cells recruits macrophages to hyperplastic regions where they promote angiogenesis and epithelial cell proliferation. Clinically, patients with increased numbers of tumor-associated macrophages have increased risk of relapse and decreased overall survival. While these previous studies demonstrate a role for macrophages during tumor initiation and progression the specific mechanisms that orchestrate the pro-tumor response are poorly understood. Our work uses numerous in vitro and in vivo models to study the dynamic interactions between mammary epithelial cells and macrophages. In an initial screen, we identified the transcription factor signal transducer and activator of transcription 5 (STAT5) as being rapidly activated in macrophages in response to factors involved in mammary gland development in vitro and have observed phospho-STAT5+ macrophages present in the developing mammary gland in vivo. To assess the role of STAT5 in macrophages during normal mammary gland development, we created a macrophage-specific conditional knockout mouse line with Cre recombinase expression driven by the Csf1r promoter. STAT5-deficient macrophages have significantly increased expression of pro-inflammatory cytokines as well as the estrogen-synthesizing enzyme aromatase. Consistent with increased estrogen production, mice carrying a macrophage-specific deletion of STAT5 (Stat5 fl/fl ; Csf1r-Cre +) show increased epithelial cell proliferation, increased mammary gland branching and impaired ductal elongation at 6 weeks of age compared to littermate controls (Stat5 fl/fl ; Csf1r-Cre -) along with increased expression of canonical ER target genes. Based on these data, we hypothesized that the loss of STAT5 in macrophages would accelerate mammary tumorigenesis. To test this, we crossed the macrophage-specific STAT5 knockout mice with a mouse model of FGFR1-induced mammary tumorigenesis. FGFR1 activation was induced in the mice for 2 weeks beginning at 6 weeks of age. Consistent with previous reports, activation of FGFR1 in mammary epithelial cells results in increased proliferation and lateral bud formation. Surprisingly, mice with STAT5-deficient macrophages show signs of accelerated tumorigenesis, with increased proliferation and numerous instances of ER+ hyperplasia in the first 2 weeks of FGFR1 activation. Future studies will focus on understanding the downstream effects of STAT5 deletion in macrophages and the therapeutic potential of targeting this pathway in vivo. All together, these data demonstrate that STAT5 is a critical factor that allows macrophages to regulate normal mammary gland development. In addition, this work illustrates that reduced STAT5 activity in macrophages can cooperate with a common genetic event in mammary epithelial cells to promote breast cancer initiation. Citation Format: Nicholas J. Brady, Michael A. Farrar, Kathryn L. Schwertfeger. Macrophage-specific deletion of STAT5 disrupts normal mammary gland development and accelerates mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B64.