Abstract
BackgroundThe 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.MethodsWe examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis.ResultsSRC-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.ConclusionsThese results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.
Highlights
The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands
To examine the effects of steroid receptor coactivator 1 (SRC-1) null mutation on mammary tumorigenesis in vivo, we created SRC1-/-;neu and SRC1+/+;neu mice and characterized mammary tumors arising in these animals following administration of PPAR or retinoid X receptor (RXR) ligands
No statistically significant differences in growth rates or number of tumors were observed between the groups. These results indicate that SRC-1 null mutation increased mammary tumor latency, decreased metastasis, and reduced the inhibitory effects of PPAR and RXR ligands in neu transgenic mice
Summary
The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. 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). The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily are activated by a variety of ligands such as fatty acids, prostaglandin J2 metabolites, fibrates, and thiazolidinedione drugs [for review see [1,2]]. Clofibrate is approved for treatment of hyperlipidemia while ciglitazone analogs are used as antidiabetic drugs Both classes of drugs have been used as experimental cancer therapies. RXR selective ligands were highly effective in preclinical models of mammary cancer
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