Abstract 2155: Acquired tamoxifen resistance sensitises breast cancer cells to bisphosphonates

Acquisition of resistance to endocrine therapies is a major limiting factor to their clinical effectiveness, resulting in disease relapse and poor prognosis. This may be due in part to the observations that acquired resistance to agents such as tamoxifen is accompanied by a gain in aggressive cellular features likely to promote disease spread and survival at metastatic sites. Bisphosphonates (BPs) are potent antiresorptive drugs used to treat osteoporosis and bone metastasis. Recent evidence also suggests that these agents may possess anti-tumour properties independently of their action on osteoclasts in a range of different tumours including breast cancers resulting in suppression of proliferation and migration and an induction of apoptosis. Here we have explored the potential of the bisphosphonate, zoledronic acid (ZOL) to suppress the aggressive phenotype of acquired endocrine-resistant breast cancer models versus their endocrine-sensitive counterparts. ER+, endocrine-sensitive MCF7 cells and their highly-proliferative, ER+, tamoxifen-resistant (‘TamR’) counterparts were exposed to increasing concentrations of ZOL (1-160μM) for 3 days and changes in growth determined by MTT assay and cell counting. Immunohistochemical analysis of Ki67 confirmed cell growth effects whilst cell cycle analysis was performed using FACS and propidium iodide. Changes in signalling pathways were investigated by Western blotting. The proliferative capacity of TamR cells was greatly suppressed by ZOL in a dose dependent manner in contrast to MCF7, where the effect was minimal (IC50 ± SD: 30 ± 4 μM (TamR) versus 150 ± 15 μM (MCF7); p Our data suggests that acquisition of resistance to tamoxifen confers a sensitivity to BPs where treatment of resistant cells with agents such as zoledronic acid results in suppression of proliferation and modulation of AKT signalling. These data suggest that BPs may exert direct anti-tumour effects on breast cancers which have relapsed on endocrine treatment. Citation Format: Dionysia Lymperatou, Christopher Smith, Wen Guo Jiang, Bronwen Evans, Stephen Hiscox. Acquired tamoxifen resistance sensitises breast cancer cells to bisphosphonates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2155.