Abstract 3718: Taxane-induced hedgehog activation promotes stemness of breast cancer cells.

Abstract

Abstract Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able to repopulate the tumor. The hedgehog (HH) signaling pathway has been shown to regulate the proliferation and survival of breast cancer stem cells, and has been shown to promote resistance to chemotherapy through the activation of multi-drug resistance and prosurvival pathways. Here we report that exposure of heterogenous breast cancer cell lines (T47D and SKBr3) to low doses (1-10nM) of docetaxel resulted in activation of HH signaling. Increased levels of sonic HH were detected in supernatants of breast cancer cells at 6- hours post-treatment. This release was accompanied by increased expression and nuclear translocation of Gli-1, peaking at 24 hours after exposure. Additionally, increased expression of the PTCH receptor was observed by western blotting in these cells 24 hours after treatment, indicating activation of a Gli-1 induced negative feeback loop. Increased mammosphere formation was observed in cells after preincubation with low dose docetaxel. Secondary sphere forming efficiency (SFE) was also increased in pretreated cells. The increase in SFE was similar to that of cell lines cultured in the presence of recombinant SHH. Additionally, the increase in SFE observed after docetaxel treatment could be blocked by the addition of sublethal doses of the hedgehog inhibitor cyclopamine. These results suggest that hedgehog pathway activation induced by docetaxel treatment could result in increased stemness of breast cancer cell lines. We propose that chemotherapy may activate stem cell signaling pathways, resulting in expansion of cancer stem cells and increased drug resistance. Citation Format: Lynn Opdenaker, Jennifer Sims-Mourtada. Taxane-induced hedgehog activation promotes stemness of breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3718. doi:10.1158/1538-7445.AM2013-3718