title: Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-β-mediated MDSC infiltration.
abstract: The oncogenic role of microRNA-155 (miR-155) in leukemia is well established but its role in other cancers, especially breast cancer, is gradually emerging. In this study we examined the effect of mir-155 loss in a well-characterized spontaneous breast cancer mouse model where Brca1 and Trp53 are deleted by K14-Cre. miR-155 is known to be up-regulated in BRCA1-deficient tumors. Surprisingly, complete loss of miR-155 (miR-155ko/ko) did not alter the tumor free survival of the mutant mice. However, we found increased infiltration of myeloid derived suppressor cells (MDSCs) in miR-155 deficient tumors. In addition, cytokine/chemokine array analysis revealed altered level of cytokines that are implicated in the recruitment of MDSCs. Mechanistically, we identified C/EBP-β, a known miR-155 target, to regulate the expression of these cytokines in the miR-155-deficient cells. Furthermore, using an allograft model, we showed that inhibition of miR-155 in cancer cells suppressed in vivo growth, which was restored by the loss of miR-155 in the microenvironment. Taken together, we have uncovered a novel tumor suppressive function of miR-155 in the tumor microenvironment, which is also dependent on miR-155 expression in the tumor cells. Because of the oncogenic as well as tumor suppressive roles of miR-155, our findings warrant caution against a systemic inhibition of miR-155 for anticancer therapy.
authors: Department of Biomedical Sciences, Department of Physiology, University of Ulsan School of Medicine, Seoul, South Korea.
authors: Sinae
authors: S
authors: Kim
authors: Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Taejeon, South Korea.
authors: Jin Hoi
authors: JH
authors: Song
authors: Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Taejeon, South Korea.
authors: Seokho
authors: S
authors: Kim
authors: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors: Peng
authors: P
authors: Qu
authors: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors: Betty K
authors: BK
authors: Martin
authors: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors: Waheed S
authors: WS
authors: Sehareen
authors: Pathology Histotechnology Laboratory, Leidos Inc., Frederick National Laboratory for Cancer, Frederick, MD, USA.
authors: Diana C
authors: DC
authors: Haines
authors: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors: Pengnian C
authors: PC
authors: Lin
authors: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors: Shyam K
authors: SK
authors: Sharan
authors: Department of Biomedical Sciences, Department of Physiology, University of Ulsan School of Medicine, Seoul, South Korea.
authors: Suhwan
authors: S
authors: Chang
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009857:Oncogenes; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse
keywords: C/EBP-beta; MDSC; breast cancer; cytokine; miR-155