PMID- 21080969 OWN - NLM STAT- MEDLINE DCOM- 20110331 LR - 20211020 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 10 DP - 2010 Nov 16 TI - Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands. PG - 629 LID - 10.1186/1471-2407-10-629 [doi] AB - 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. FAU - Han, Ji Seung AU - Han JS AD - University of Illinois Cancer Center, Chicago, 60612, USA. FAU - Crowe, David L AU - Crowe DL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20101116 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (AGN 194204) RN - 0 (Antineoplastic Agents) RN - 0 (Fatty Acids, Unsaturated) RN - 0 (Peroxisome Proliferator-Activated Receptors) RN - 0 (Retinoid X Receptors) RN - 0 (Tetrahydronaphthalenes) RN - 0 (Thiazolidinediones) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - EC 2.3.1.48 (Ncoa1 protein, mouse) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) RN - HPN91K7FU3 (Clofibrate) RN - U8QXS1WU8G (ciglitazone) SB - IM MH - Animals MH - Antineoplastic Agents/*pharmacology MH - CREB-Binding Protein/genetics/metabolism MH - Cell Differentiation/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Chromatin Assembly and Disassembly/drug effects MH - Clofibrate/pharmacology MH - Fatty Acids, Unsaturated/pharmacology MH - Female MH - Gene Expression Regulation, Neoplastic MH - *Genes, erbB-2 MH - Humans MH - Mammary Neoplasms, Experimental/enzymology/genetics/pathology/*prevention & control MH - Mammary Tumor Virus, Mouse/*genetics MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - Neoplasm Invasiveness MH - Nuclear Receptor Coactivator 1/*deficiency/genetics MH - Peroxisome Proliferator-Activated Receptors/*agonists/genetics/metabolism MH - Promoter Regions, Genetic MH - Retinoid X Receptors/agonists/genetics/metabolism MH - Tetrahydronaphthalenes/pharmacology MH - Thiazolidinediones/pharmacology MH - Time Factors MH - Transfection MH - Tumor Burden/drug effects PMC - PMC2999618 EDAT- 2010/11/18 06:00 MHDA- 2011/04/01 06:00 PMCR- 2010/11/16 CRDT- 2010/11/18 06:00 PHST- 2010/04/10 00:00 [received] PHST- 2010/11/16 00:00 [accepted] PHST- 2010/11/18 06:00 [entrez] PHST- 2010/11/18 06:00 [pubmed] PHST- 2011/04/01 06:00 [medline] PHST- 2010/11/16 00:00 [pmc-release] AID - 1471-2407-10-629 [pii] AID - 10.1186/1471-2407-10-629 [doi] PST - epublish SO - BMC Cancer. 2010 Nov 16;10:629. doi: 10.1186/1471-2407-10-629.