Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

• Published in: BMC cancer Vol. 10; no. 1; p. 629
• Main Authors: Han, Ji Seung, Crowe, David L
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16.11.2010; BioMed Central; BMC
• Subjects: Animals; Antineoplastic Agents - pharmacology; Breast cancer; Cancer therapies; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chromatin Assembly and Disassembly - drug effects; Clofibrate - pharmacology; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; Development and progression; Fatty Acids, Unsaturated - pharmacology; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Genetic aspects; Humans; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - prevention & control; Mammary Tumor Virus, Mouse - genetics; Medical research; Mice; Mice, Knockout; Mice, Transgenic; Neoplasm Invasiveness; Nuclear Receptor Coactivator 1 - deficiency; Nuclear Receptor Coactivator 1 - genetics; Peroxisome Proliferator-Activated Receptors - agonists; Peroxisome Proliferator-Activated Receptors - genetics; Peroxisome Proliferator-Activated Receptors - metabolism; Peroxisomes; Physiological aspects; Promoter Regions, Genetic; Proteins; Retinoid X Receptors - agonists; Retinoid X Receptors - genetics; Retinoid X Receptors - metabolism; Rodents; Tetrahydronaphthalenes - pharmacology; Thiazolidinediones - pharmacology; Time Factors; Transcriptional coactivators; Transfection; Tumor Burden - drug effects; Tumors
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-10-629

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. We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. 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. These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.