title: Tumor STAT1 transcription factor activity enhances breast tumor growth and immune suppression mediated by myeloid-derived suppressor cells.
abstract: Previous studies had implicated the IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33(+) myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hix
authors.forename: John
authors.initials: J
authors.lastname: Karavitis
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Khan
authors.forename: Yihui H
authors.initials: YH
authors.lastname: Shi
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; C494080:Stat1 protein, mouse