Abstract P6-14-11: ß-Catenin Inhibitor SST-024 Can Sensitize Breast Cancer Tumor Initiation Cells (TICs) to Ionized Radiotherapy

Abstract

Abstract Recent studies have shown that tumor initiation cells (TICs) are more resistant to ionized radiotherapy (IR) than differentiated cancer cells. In our lab, we have previously shown that aberrant Wnt signaling can contribute to radio-resistance of TICs in breast cancer. Herein, we use SST-024 (StemSynergy), an inhibitor of ß-catenin and WNT signaling, to test if pharmacologic inhibition of ß-catenin can sensitize breast cancer TICs to IR. Sum-149, an inflammatory breast cancer cell line, Sum-159, a non-inflammatory basal-type breast cancer cell line and IBC-3, a short-term cultured inflammatory breast cancer sample were used in these studies. We found that SST-024 inhibited Sum-149 mammosphere formation, a surrogate for TIC growth in vitro, at IC-50 0.3 nM while IC-50 for Sum-159 was 3 nM and IC-50 for IBC-3 was 4 nM. Similar efficacy against TICs was seen in assessments of alternative TIC surrogates including aldefluor staining by flow cytometry and CD44+CD24- marked cells. On immunoblot analysis SST-024 down-regulated unphosphorylated, active B-catenin and downstream target c-myc as well as EMT marks, including N-cadherin, Snail, Twist and Slug, and DNA repair regulator ATM. Moreover, standard monolayer and 3D mammospheres clonogenic assays demonstrate significant radiosensitization of SUM-149 TICs (mammospheres) as well as monolayer colony formation. In summary, SST-024 demonstrates significant efficacy against inflammatory breast cancer TICs and sensitize both TICs and non-TICs to IR implying targeting Wnt β-catenin signaling may be a feasible strategy to radiosensitize breast cancer TICs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-11.