title: Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands.
abstract: BACKGROUND
  The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies.
  
  
  METHODS
  We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis.
  
  
  RESULTS
  SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter.
  
  
  CONCLUSIONS
  These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.
authors.affiliation: University of Illinois Cancer Center, Chicago, 60612, USA.
authors.forename: Ji Seung
authors.initials: JS
authors.lastname: Han
authors.forename: David L
authors.initials: DL
authors.lastname: Crowe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D056920:Nuclear Receptor Coactivator 1 / Q000172:deficiency* / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047488:Retinoid X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C430898:AGN 194204; D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D047492:Peroxisome Proliferator-Activated Receptors; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D045162:Thiazolidinediones; D050882:CREB-Binding Protein; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D002994:Clofibrate; C039671:ciglitazone