Novel link between estrogen receptor α and hedgehog pathway in breast cancer

Ligand-dependent constitutive activation of the hedgehog (Hh) pathway is important in the development of various carcinomas including breast cancer. A link between estrogen receptor α (ERα) and the Hh pathway in human breast cancer is shown here for the first time. In ERα-positive cells, estrogen depletion decreased the expression of sonic hedgehog (Shh), a ligand of the Hh pathway, while estrogen supplementation triggered Shh up-regulation. This estrogen-induced Shh expression activated the Hh pathway in a ligand-dependent manner, and increased cell proliferation. These effects were suppressed by ERα inhibitors, including ICI 182,780 (ICI), the dominant negative form of ERα and small interfering RNA (siRNA) against ERα. Consistent with the in vitro data, a positive correlation between ERα and Shh expression was found in breast cancer tissues. These data suggest that ERα regulates the Hh pathway through Shh induction, and promotes breast cancer development.