title: Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis.
abstract: The tumor microenvironment (TME), the dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphologic and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAG) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an increased number of Lin-CD24+/CD49+enriched mammary gland stem cells (MaSC), suggesting deregulated tissue homeostasis in TAGs. Comparative transcriptome analysis of TAGs and contralateral control glands coupled with meta-analysis on differentially expressed genes with two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1. Knockdown of STAT1 in cancer-associated fibroblast (CAF) cocultured with human breast cancer cells altered cancer cell proliferation, indicating a role for STAT1 as a stromal contributor of tumorigenesis. Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progressionin vivoFinally, cotreatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Taken together, these results demonstrate that stromal STAT1 expression promotes tumor progression and is a potential therapeutic target for breast cancer.Implications:Tumors induce stromal STAT1-dependent cytokine secretion that promotes tumor cell proliferation and can be targeted using clinically-approved inhibitors of STAT1.Mol Cancer Res; 15(5); 585-97. ©2017 AACR.
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Zellmer
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Schnepp
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Fracci
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Howe
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana. szhang8@nd.edu.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology* / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D050794:STAT1 Transcription Factor / Q000235:genetics*; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human