Zhang Xiaomei, Harrington Nikesha, Moraes Ricardo C, Wu Meng-Fen, Hilsenbeck Susan G, Lewis Michael T
Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Breast Cancer Res Treat. 2009 Jun;115(3):505-21. doi: 10.1007/s10549-008-0093-3. Epub 2008 Jun 19.
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.
异常的刺猬信号通路与大约20%-25%的所有癌症的发生有关，尤其是软组织癌症。小鼠的遗传学证据以及人类乳腺癌标本的免疫定位研究表明，失调的刺猬信号通路可能促成乳腺癌的发生。确实，最近的两项研究表明，环杷明（一种靶向平滑肌瘤（SMO）蛋白的强效刺猬信号通路拮抗剂）会损害某些人乳腺癌细胞系的锚定依赖性生长。然而，环杷明在生长抑制所需剂量（≥10 microM）下的特异性仍是一个悬而未决的问题。在本文中，我们证明，包括环杷明和第二种化合物CUR0199691在内的刺猬信号通路拮抗剂在高剂量时可抑制雌激素受体（ER）阳性和ER阴性致瘤性乳腺癌细胞的生长。然而，我们的结果表明，对于大多数乳腺癌细胞系，这些化合物的生长抑制可能与可检测到的Smo基因表达无关。相反，我们的结果表明，环杷明和CUR0199691在生长抑制所需剂量下具有独特的次要分子靶点，这些靶点与刺猬信号通路无关。
