title: Peroxisome proliferator-activated receptor alpha expression is regulated by estrogen receptor alpha and modulates the response of MCF-7 cells to sodium butyrate.
abstract: Peroxisome proliferator-activated receptors are ligand-activated transcription factors with a potential role in cancer. We investigated peroxisome proliferator-activated receptor alpha expression in breast cancer cell lines and showed a relationship between mean peroxisome proliferator-activated receptor alpha and estrogen receptor alpha mRNA levels in estrogen receptor alpha positive breast cancer cells. Transfection of estrogen receptor alpha into the estrogen receptor alpha negative cell line, MDA-MB-231 decreased peroxisome proliferator-activated receptor alpha mRNA and conversely inhibition of estrogen receptor alpha by ICI-182 780 in estrogen receptor alpha positive, MCF-7 cells increased peroxisome proliferator-activated receptor alpha mRNA levels. Estrogen receptor alpha levels can be modulated by histone deacetylase inhibitors and such agents are in clinical trials for cancer treatment. We found the histone deacetylase inhibitor, sodium butyrate, increased peroxisome proliferator-activated receptor alpha mRNA levels within 4h of treatment. Peroxisome proliferator-activated receptor alpha modulation was independent of estrogen receptor alpha, as a similar increase was observed in the estrogen receptor alpha negative MDA-MB-231 cells. To further investigate the relationship between sodium butyrate and peroxisome proliferator-activated receptor alpha expression, we created an MCF-7 cell line that conditionally over-expresses human peroxisome proliferator-activated receptor alpha. Over-expression of the peroxisome proliferator-activated receptor protected MCF-7 cells from sodium butyrate-mediated inhibition of proliferation and attenuated sodium butyrate-mediated induction of histone deacetylase 3 mRNA, indicating that elevated levels of peroxisome proliferator-activated receptor alpha may reduce the sensitivity of cells to histone deacetylase inhibitors. The estrogen receptor alpha dependence of peroxisome proliferator-activated receptor alpha levels may be significant since estrogen receptor alpha negative breast cancer cells are associated with a more aggressive phenotype. Our studies also suggest that peroxisome proliferator-activated receptor alpha levels may be a marker of breast cancer cell sensitivity to histone deacetylase inhibitors.
authors.affiliation: School of Pharmacy, University of Queensland, Steele Building, Brisbane, Qld 4072, Australia.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Faddy
authors.forename: Jodie A
authors.initials: JA
authors.lastname: Robinson
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Holman
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D002087:Butyrates; D047628:Estrogen Receptor alpha; D006655:Histone Deacetylases; D047493:PPAR alpha; D000099186:Histone Deacetylase 3