title: A positive role of DBC1 in PEA3-mediated progression of estrogen receptor-negative breast cancer.
abstract: Deleted in Breast Cancer 1 (DBC1), a negative regulator of deacetylase SIRT1, has been shown to act as an estrogen receptor α (ER) coactivator that has a key role in ER transcription complex assembly and estrogen-dependent breast cancer cell proliferation. However, little is known about its physiological role and mechanism of action in ER-negative breast cancer cells. Here we report that DBC1 functions as a coactivator for the oncogenic ETS transcription factor PEA3 to promote ER-negative breast cancer progression. DBC1 is required for the expression of PEA3 target genes and for recruitment of PEA3 and RNA polymerase II to PEA3 target promoters. We also demonstrated that acetylation of PEA3 stimulates its DNA binding and association with DBC1 by disrupting the intramolecular interaction of PEA3. The molecular mechanism underlying DBC1 function in PEA3-mediated transcription involves inhibition of SIRT1 interaction with PEA3 and of SIRT1-mediated deacetylation of PEA3. Moreover, DBC1 depletion inhibited the tumorigenic properties of ER-negative breast cancer cells in vitro and in vivo. Importantly, increased DBC1 expression correlated with shorter relapse-free survival of ER-negative breast cancer patients. Our results firmly established DBC1 as a critical coactivator of PEA3 and as a key player in PEA3-mediated breast cancer progression.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: E J
authors.initials: EJ
authors.lastname: Yu
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Seo
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000502:physiology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000737:chemistry / Q000209:etiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D011960:Receptors, Estrogen / Q000032:analysis*; D056564:Sirtuin 1 / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; C527450:CCAR2 protein, human; C079853:ETV4 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011960:Receptors, Estrogen; C447939:SIRT1 protein, human; D056564:Sirtuin 1