title: RelA-Induced Interferon Response Negatively Regulates Proliferation.
abstract: Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Bose S
authors.initials: BS
authors.lastname: Kochupurakkal
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Tony
authors.initials: T
authors.lastname: Hua
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Aedin C
authors.initials: AC
authors.lastname: Culhane
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Cytology, Clinical Hospital Center Rijeka, Rijeka, Croatia.
authors.forename: Koraljka
authors.initials: K
authors.lastname: Rajkovic-Molek
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Lazaro
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Debajit K
authors.initials: DK
authors.lastname: Biswas
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: J Dirk
authors.initials: JD
authors.lastname: Iglehart
mesh_terms: D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology; D005187:Fallopian Tubes / Q000166:cytology; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007372:Interferons / Q000494:pharmacology*; D035683:MicroRNAs / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D035683:MicroRNAs; D016160:Retinoblastoma Protein; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; D007372:Interferons; D051358:Cyclin-Dependent Kinase 4