Breast and
prostate cancer are leading causes of
cancer death in the Western world.
Hormone ablation is the primary
therapy for invasive disease, but the tumour often recurs in an
androgen or oestrogen receptor negative form for which novel
therapies are sought urgently. The
vitamin D receptor (VDR) may provide an important alternative therapeutic target. However,
cancer cell line models from these tissues display a range of sensitivities to the antiproliferative effects of 1alpha,25dihydroxyvitamin D3 (1alpha,25(
OH)2D3). The reason for apparent 1alpha,25(
OH)2D3 insensitivity is currently unknown and we have investigated epigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear
co-repressors have associated
histone deacetylase (HDAC) activity, which keeps
chromatin in a closed, transcriptionally silent state. We have found that the aggressive
cancer cell lines with relative insensitivity to 1alpha,25(
OH)2D3 have elevated nuclear
co-repressor levels. For example, PC-3
prostate cancer cells have a significant 1.8-fold elevation in the
co-repressor SMRT compared to normal epithelial cells (P < 0.05). We believe that a combination of elevated
co-repressor level with reduced VDR content can cause 1alpha,25(
OH)2D3 resistance. Consistent with this, we have shown that combining a low dose of
HDAC inhibitor Trichostatin A (15 nM
TSA) with 1alpha,25(
OH)2D3 (100 nM) synergistically inhibits the proliferation of PC-3 prostate and MDA-MB-231
breast cancer cell lines. The inhibition of proliferation was potentiated further by treating cells with
19-nor-hexafluoride vitamin D3 analogues instead of 1alpha,25(
OH)2D3, plus
TSA. For example, the combination of 1alpha,25(
OH)2D3 and
TSA-inhibited MDA-MB-231 cell proliferation by 38% (+/-5%), whereas Ro26-2198 (1alpha,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3) and
TSA inhibited growth by 62% (+/-2%). Therapeutically the hypercalcaemic side effects associated with 1alpha,25(
OH)2D3 could be minimized by combining low doses of potent 1a,25(
OH)2D3 analogues with
HDAC inhibitors as a novel anticancer regime for
hormone-insensitive prostate and
breast cancer.