Peroxisome proliferator-activated receptor α expression is regulated by estrogen receptor α 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 α expression in breast cancer cell lines and showed a relationship between mean peroxisome proliferator-activated receptor α and estrogen receptor α mRNA levels in estrogen receptor α positive breast cancer cells. Transfection of estrogen receptor α into the estrogen receptor α negative cell line, MDA-MB-231 decreased peroxisome proliferator-activated receptor α mRNA and conversely inhibition of estrogen receptor α by ICI-182 780 in estrogen receptor α positive, MCF-7 cells increased peroxisome proliferator-activated receptor α mRNA levels. Estrogen receptor α 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 α mRNA levels within 4 h of treatment. Peroxisome proliferator-activated receptor α modulation was independent of estrogen receptor α, as a similar increase was observed in the estrogen receptor α negative MDA-MB-231 cells. To further investigate the relationship between sodium butyrate and peroxisome proliferator-activated receptor α expression, we created an MCF-7 cell line that conditionally over-expresses human peroxisome proliferator-activated receptor α. 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 α may reduce the sensitivity of cells to histone deacetylase inhibitors. The estrogen receptor α dependence of peroxisome proliferator-activated receptor α levels may be significant since estrogen receptor α negative breast cancer cells are associated with a more aggressive phenotype. Our studies also suggest that peroxisome proliferator-activated receptor α levels may be a marker of breast cancer cell sensitivity to histone deacetylase inhibitors.