Abstract 3926: Abrogating tamoxifen resistance with the ribonucleoside analog, 8-amino adenosine

Abstract

Abstract Hormone therapy is a prevalent treatment of choice for patients with estrogen receptor alpha (ERα) positive breast cancers. Unfortunately, due to resistance, many women do not benefit from these forms of therapy. AIB1 is a transcriptional co-activator that plays an important role in resistance to hormone therapy. Depending on the cell/gene context, agents such as tamoxifen either stimulate or antagonize the transcriptional activities of ERα. Tamoxifen binding alters ERα to an intermediate conformation with affinity for both co-activators and co-repressors, causing the conformation to be dependent on co-regulator levels in the cell milieu. The stoichiometric balance between AIB1 and co-repressors is a key determinant of tamoxifen resistance. Additionally, cross-talk between ERα and growth factor (GF) signaling further manipulates ERα activity and responsiveness to hormone therapy, particularly in cells with high AIB1 levels. Of the receptor signaling transducers, AKT, ERK, and p38 are key players in resistance. We hypothesized that strategies to target the stoichiometric balance of AIB1 to co-repressors would be clinically beneficial for abrogating tamoxifen resistance. Furthermore, it has been demonstrated that agents that are able to interfere with the ERα/GF crosstalk are also highly advantageous for abrogating resistance to tamoxifen. We have shown that the ribonucleoside analog, 8-aminoadenosine (8-NH2-Ado) is a transcription inhibitor. As such, it is expected to primarily deplete the expression of the small percentage (∼5%) of gene transcripts with short-half lives, such as AIB1. We have demonstrated that treatment of MCF-7 and BT-474 cells with non-tumoricidal concentrations of 8-NH2-Ado (1 µM) decreased AIB1 protein levels. Furthermore, using in vitro kinase assays, we demonstrated the active metabolite of 8-NH2-Ado is a selective inhibitor of MEK1, 2, and 6. An initial analysis of 4-hydroxytamoxifen dose response in two different tamoxifen resistant breast cancer cell lines, MCF-7/HER-2:18 and BT-474, demonstrated non-tumoricidal analog concentrations were able to reduce the dose of 4-hydroxytamoxifen needed to inhibit proliferation in these cells. Additionally, 8-NH2-Ado inhibited AKT and ERK1/2 activity in these cells. In conclusion, AIB1 and GF signaling molecules are attractive targets for reversing resistance to hormone therapy. Our results suggest that treating ERα positive breast cancer with combinations of tamoxifen and 8-NH2-Ado would be an effective strategy to overcome tamoxifen resistance. 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 3926. doi:1538-7445.AM2012-3926