Targeting Breast Cancer Recurrence via Hedgehog-Mediated Sensitization of Breast Cancer Stem Cells.

摘要

Breast cancer recurrence is a major clinical obstacle that accounts for greater than 95% of breast cancer mortality in the United States. It is believed to be the result of a subset of breast tumor cells commonly referred to as tumor stem cells that are characterized by broad-spectrum resistance to cytotoxic therapeutics and tumorigenicity. The broad-spectrum resistance to agents that preferentially target proliferating cells is consistent with reports indicating that tumor stem cells are very slow-growing or quiescent cells. Previously we have reported that hyper-activation of the hedgehog signaling pathways subverts quiescence in mammary stem cells. The goal of the current study was to determine if modulation of hedgehog signaling would affect the kinetics of the mammary regenerative cycle and the proliferative activity of mammary stem cells and breast tumor stem cells. Using a combination of genetic and pharmacologic approaches we present data indicating that small molecule modulators of Smoothened are able to bi-directionally regulate hedgehog signalling in vivo and that pharmacologic activation of hedgehog signaling phenocopies the effects of Ptch1 heterozygosity during mammary development and regenerative stasis. Additionally we find that hedgehog activation promotes stem cell proliferation and luminal epithelial cell fate. Finally we present data indicating that taxane resistance can be subverted via pharmacologic activation of hedgehog signaling with SAG1. Together these studies indicate that hedgehog signaling in tumor stem cell populations may subvert quiescence and broad-spectrum chemo-resistance.