Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo).
Altered hedgehog signaling is implicated in the development of approximately 20-25% of all cancers, especially those of soft tissues. Genetic evidence in mice as well as immunolocalization studies in human breast cancer specimens suggest that deregulated hedgehog signaling may contribute to breast cancer development. Indeed, two recent studies demonstrated that anchorage-dependent growth of some human breast cancer cell lines is impaired by cyclopamine, a potent hedgehog signaling antagonist targeting the Smoothened (SMO) protein. However, specificity of cyclopamine at the dosage required for growth inhibition (> or =10 microM) remained an open question. In this paper we demonstrate that hedgehog signaling antagonists, including cyclopamine, and a second compound, CUR0199691, can inhibit growth of estrogen receptor (ER)-positive and ER-negative tumorigenic breast cancer cells at elevated doses. However, our results indicate that, for most breast cancer cell lines, growth inhibition by these compounds can be independent of detectable Smo gene expression. Rather, our results suggest that cyclopamine and CUR0199691 have unique secondary molecular targets at the dosages required for growth inhibition that are unrelated to hedgehog signaling.
Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Xiaomei
X
Zhang
Nikesha
N
Harrington
Ricardo C
RC
Moraes
Meng-Fen
MF
Wu
Susan G
SG
Hilsenbeck
Michael T
MT
Lewis
D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology*
D053823:Hedgehog Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D002784:Cholesterol; C000541:cyclopamine