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Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo)

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Abstract

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 (≥10 μM) 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.

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Acknowledgements

This work was supported, in part, by a Department of Defense IDEA Award (DAMD17-00-1-0477), a SPORE Developmental Project Grant (P50 CA50183), and a National Institutes of Health Grant (P01- CA30195). The authors thank Drs. Frederick de Sauvage (Genentech Inc. South San Francisco, CA) and Stephen Gould (Curis Inc. Cambridge MA) for providing CUR0199691 and recombinant SHH-N ligand for this study, as well as for critical evaluation of the data. We thank Dr. Matthew Herynk for advice regarding cell culture, and Dr. Andra Frost for helpful discussions, provision of a Smo primer/probe set used previously in her laboratory, and for critical evaluation of the data.

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  1. Lester and Sue Smith Breast Center and the Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room N1210, BCM600, Houston, TX, 77030, USA

    Xiaomei Zhang, Nikesha Harrington, Ricardo C. Moraes, Meng-Fen Wu, Susan G. Hilsenbeck & Michael T. Lewis

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  1. Xiaomei Zhang
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Correspondence to Michael T. Lewis.

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Zhang, X., Harrington, N., Moraes, R.C. et al. Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo) . Breast Cancer Res Treat 115, 505–521 (2009). https://doi.org/10.1007/s10549-008-0093-3

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  • DOI: https://doi.org/10.1007/s10549-008-0093-3

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