Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy.

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 pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4-24 h after DOC treatment. This activation had little effect on the bulk of the tumor cell population as inhibition of HH signaling failed to increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemness markers as well as mammosphere formation were observed after treatment with DOC suggesting an increase in the breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced by DOC treatment does not have a chemosensitizing effect on the heterogeneous tumor population, but may be required for survival and expansion of breast cancer stem cells after chemotherapy.