title: Cyclopamine is a novel Hedgehog signaling inhibitor with significant anti-proliferative, anti-invasive and anti-estrogenic potency in human breast cancer cells.
abstract: Stimulation of Hedgehog (Hh) signaling induces carcinogenesis or promotes cell survival in cancers of multiple organs. In epithelial cancer with aberrant Hedgehog activation, abrogation of Hedgehog signaling by cyclopamine, a naturally occurring Hedgehog-specific small-molecule inhibitor, causes profound inhibition of tumor growth. In the present study, cyclopamine displayed a significant potency in suppressing the proliferation of both estrogen-responsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. Cyclopamine induced a robust G1 cell cycle arrest and elicited notable effects on the expression of cyclin D1 through modulation of the MAPK/ERK signaling pathway. Cyclopamine also inhibited the invasive ability of both breast cancer cell lines by suppressing the expression levels of NF-κB, MMP2 and MMP9 protein. Furthermore, in estrogen-responsive MCF-7 cells, cyclopamine significantly downregulated the production of estrogen receptor-α protein. Our results implicate cyclopamine as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of breast cancer.
authors.affiliation: Key Laboratory of Radiation Biology, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123; ; Department of Radiation Oncology, The Fourth Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214062, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Che
authors.forename: Fu-Zheng
authors.initials: FZ
authors.lastname: Zhang
authors.forename: Chao-Qian
authors.initials: CQ
authors.lastname: Zhao
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Hu
authors.forename: Sai-Jun
authors.initials: SJ
authors.lastname: Fan
keywords: MAPK/ERK; breast cancer; cyclopamine; estrogen receptor-α; invasion; proliferation