Abstract 4704: Effects of the HDAC inhibitor S78454/PCI-24781 on ER signalling in ERα-positive antiestrogen-sensitive and -resistant breast cancer cells

Abstract

Abstract Background: Estrogen receptors (ER) drive breast cancer development through the regulation of gene transcription and the inhibition of ER signalling is the main therapeutic strategy for hormone-dependent breast cancers. Selective ER modulators (such as tamoxifen) or aromatase inhibitors are commonly administered to patients. However, de novo and acquired resistance are frequently observed and combinatorial treatments are required to bypass this phenomenon. Acetylation plays a key role in estrogen signalling by regulating ERα and ERα expression and activity (for a recent review see Linares et al, J. Biomed. Biotech. 2011). This post-translational mark is removed by histone deacetylases (HDACs) whose enzymatic activity could be blocked by specific HDAC inhibitors (HDIs). Interestingly, it has been shown that HDIs are able to regulate ER signalling and to potentiate the anti-tumor effects of anti-estrogens in ER-positive breast cancer cells. In this study, we analyzed the effects of a new hydroxamic acid HDI S78454 on several cellular parameters regulated by estrogens in ERα expressing MCF-7 breast cancer cells. Method: The following parameters were investigated both in sensitive and in antiestrogen-resistant MCF7 cells, that we developed in our laboratory: 1) ERα expression at the mRNA and protein levels by quantitative RT-PCR and western blot, respectively 2) transcriptional activity of ERα by quantifying the expression of several estrogen-regulated mRNAs 3) HDAC expression at the mRNA level and 4) 2D cell proliferation using MTS assay. Results: In MCF-7 breast cancer cells, S78454 decreased ERα expression, modulated gene expression (E2 target genes, HDACs and HDI-regulated genes) and inhibited cell proliferation. S78454 globally behaved as the reference HDIs yielding very similar amplitudes on the parameters that we have analyzed with EC50 being comprised between those of Vorinostat and Panobinostat. Interestingly, the IC50 of S78454 on MCF-7 cell proliferation was lower in cells treated with antiestrogens than in control cells or in cells treated with E2. Moreover, in antiestrogen-resistant MCF-7 cells that we developed in our laboratory, S78454 was able to significantly restore the sensitivity to the pure antiestrogen Fulvestrant. Conclusions and perspectives: Our findings suggest that in breast tumor cells, S78454 exhibits antiproliferative effects, can exert synergistic effects with antiestrogens and can restore antiestrogen-sensitivity in a model of antiestrogen-resistant MCF7 cell line. These results suggest that the combination of S78454 and antiestrogens could be valuable in the treatment of breast cancers resistant to hormonal therapies. This effect should be validated in vivo on tumor xenografts. In addition, it would be interesting to investigate whether S78454 also reinforces the anti-growth factor activity of antiestrogens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4704. doi:1538-7445.AM2012-4704