Efficacy of Histone Deacetylase and Estrogen Receptor Inhibition in Breast Cancer Cells Due to Concerted down Regulation of Akt

Hormonal therapy resistance remains a considerable barrier in the treatment ofbreast cancer. Activation of the Akt-PI3K-mTOR pathway plays an important rolein hormonal therapy resistance. Our recent preclinical and clinical studiesshowed that the addition of a histone deacetylase inhibitor re-sensitizedhormonal therapy resistant breast cancer to tamoxifen. As histone deacetylasesare key regulators of Akt, we evaluated the effect of combined treatment withthe histone deacetylase inhibitor PCI-24781 and tamoxifen on Akt in breastcancer cells. We demonstrate that while both histone deacetylase and estrogenreceptor inhibition down regulate AKT mRNA and protein, their concerted effortresults in down regulation of AKT activity with induction of cell death. Histonedeacetylase inhibition exerts its effect on AKT mRNA through an estrogenreceptor-dependent mechanism, primarily down regulating the most abundantisoform AKT1. Although siRNA depletion of AKT modestly induces cell death, whencombined with an anti-estrogen, cytotoxicity is significantly enhanced. Thus,histone deacetylase regulation of AKT mRNA is a key mediator of this therapeuticcombination and may represent a novel biomarker for predicting response to thisregimen.