1471-2407-10-629.pdf (1.67 MB)
Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands
journal contributionposted on 2011-05-11, 00:00 authored by Ji S. Han
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.
We thank Dr. Jianming Xu for SRC1-/- mice, Dr. Ronald Evans for SRC-1 and CBP expression vectors, and Dr. Roshantha Chandraratna for AGN194204. This study was supported by American Institute for Cancer Research grant 05A026 to DLC.
Publisher StatementThe definitive version is available through BioMed Central at DOI: 10.1186/1471-2407-10-629. © 2010 Han and Crowe; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.