Hedgehog Signal Transduction Inhibitors in Breast Cancer Treatment and Prevention

摘要

Mutations in at least two hedgehog signal transduction network genes leads to defects in mammary gland development. These mutations can cause enhanced hedgehog signaling in some organs. Data suggest activated hedgehog signaling may contribute to neoplasia and that hedgehog signaling inhibitors may be useful in breast cancer treatment. We find (1) that constitutive activation of hedgehog signaling by overexpression of the Smoothened effector protein in transgenic mice leads to increased proliferation and cancer-like developmental defects. (2) hedgehog signaling inhibitors such as cyclopamine slow or prevent breast cancer cell growth (MCF7 and MDA231) but do not alter 'normal' cell (MCF10A). In addition, inhibitors show no measurable effect on normal mammary gland development. (3) Unexpectedly, Ptcl-induced defects are not inhibited or reverted by treatment with specific inhibitors of hedgehog signaling under the conditions tested. Our data suggest a role for hedgehog signaling in breast cancer and that hedgehog signaling inhibitors may be useful in breast cancer treatment.