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

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.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. PPARs have functional domains for DNA and ligand binding and interact with recognition sequences in the promoter regions of their target genes to regulate transcription [3]. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily [4]. Natural and synthetic ligands for RXRs, such as, AGN194204 have been characterized, and heterodimerization with PPARs greatly enhances DNA binding and transcriptional activation [5-7]. RXR selective ligands were highly effective in preclinical models of mammary cancer.Ligand binding to PPARs 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, produ