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Zhang X, Harrington N, Moraes RC, Wu MF, Hilsenbeck SG, Lewis
MT.
Cyclopamine inhibition of human breast cancer cell
growth independent of Smoothened (Smo).
Breast Cancer Res Treat. 2008 Jun 19.
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.
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 muM) 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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