Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Oncogene. 2011 Oct 27;30(43):4437-46. doi: 10.1038/onc.2011.145. Epub 2011 May 2.
Breast cancer is genetically and clinically heterogeneous. Triple negative breast cancer (TNBC) is a subtype of breast cancer that is usually associated with poor outcome and lack of benefit from targeted therapy. We used microarray analysis to perform a pathway analysis of TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), low density lipoprotein receptor-related protein 6 and transcription factor 7 (TCF7) was observed in TNBC, and we directed our focus to the Wnt pathway receptor, FZD7. To validate the function of FZD7, FZD7shRNA was used to knock down FZD7 expression. Notably, reduced cell proliferation and suppressed invasiveness and colony formation were observed in TNBC MDA-MB-231 and BT-20 cells. Study of the possible mechanism indicated that these effects occurred through silencing of the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of β-catenin and decreased transcriptional activity of TCF7. In vivo studies revealed that FZD7shRNA significantly suppressed tumor formation, through reduced cell proliferation, in mice bearing xenografts without FZD7 expression. Our findings suggest that FZD7-involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC, and thus, FZD7 shows promise as a biomarker and a potential therapeutic target for TNBC.
乳腺癌在遗传和临床上具有异质性。三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，通常与不良预后和缺乏靶向治疗获益相关。我们使用微阵列分析比较了 TNBC 与非三阴性乳腺癌（non-TNBC）的通路分析。在 TNBC 中观察到几个 Wnt 通路基因（如 frizzled 同源物 7（FZD7）、低密度脂蛋白受体相关蛋白 6 和转录因子 7（TCF7））的过表达，我们将重点放在 Wnt 通路受体 FZD7 上。为了验证 FZD7 的功能，使用 FZD7shRNA 敲低 FZD7 的表达。值得注意的是，在 TNBC MDA-MB-231 和 BT-20 细胞中观察到细胞增殖减少、侵袭性和集落形成受到抑制。对可能的机制的研究表明，这些效应是通过沉默经典 Wnt 信号通路发生的，这表现在β-catenin 的核积累减少和 TCF7 的转录活性降低。体内研究表明，在没有 FZD7 表达的情况下，FZD7shRNA 通过减少细胞增殖显著抑制了携带异种移植物小鼠的肿瘤形成。我们的研究结果表明，FZD7 参与的经典 Wnt 信号通路对于 TNBC 的肿瘤发生是必不可少的，因此，FZD7 有望成为 TNBC 的生物标志物和潜在治疗靶点。
