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Brady
Nicholas Brady

E-mail:brad0336@umn.edu

Thesis Advisor: Kaylee Schwertfeger

Year entered: 2011

Degrees received:
B.A., Boston University, Boston, MA, 2008

Honors and Awards:

  • Graduate School Fellowship: 2011 - 2012
  • Pre-doctoral trainee, Cancer Biology Training Grat, 2013-2015
  • MICaB Student Travel Award: 2013
  • MICaB Student Representative: 2013-2014
  • Outstanding Performance Award for Teaching Assistants: 2014
  • Basic Science Scholar, San Antonio Breast Cancer Symposium: 2014
  • Abstract selected for oral presentation, San Antonio Breast Cancer Symposium: 2014
  • Doctoral Dissertation Fellowship: 2015-2016
  • CTSI Translational Research Development Program Grant: 2015-2017


Thesis research:
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. 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. Moreover, mice carrying a macrophage-specific deletion of STAT5 (Stat5 fl/fl ; Csf1r-Cre +) show increased epithelial cell proliferation and impaired ductal elongation at 6 weeks of age compared to littermate controls (Stat5 fl/fl ; Csf1r-Cre -) and show increased expression of estrogen receptor 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 or 4 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 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.

Publications:

  • Farooqui M, Bohrer LR, Brady NJ, Chuntova P, Kemp SE, Wardwell T, Nelson AC, Schwertfeger KL. “Fibroblast Growth Factor Receptor-Mediated Regulation of Epiregulin Contributes to EarlyStage Breast Tumorigenesis.”  Molecular Cancer.  In press.
  • Bohrer LR, Chuntova P, Bade LK, Beadnell TC, Leon RP, Brady NJ, Ryu Y, Goldberg JE, Schmechel SC, Koopmeiners JS, McCarthy JB, Schwertfeger KL. 2014. Activation of the FGFR-STAT3 Pathway in Breast Cancer Cells Induces a Hyaluronan-Rich Microenvironment That Licenses Tumor Formation.  Cancer Research.  74(1), 374-386.
  • Brady NJ*, Chuntova P*, Bade LK, Schwertfeger KL. 2013. The FGF/FGFR signaling axis as a therapeutic target in breast cancer. Expert Review of Endocrinology & Metabolism.  8(4), 391-402.