LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy

• DOI: 10.1073/pnas.0911220107
• Publication Date: 2010-03-02T04:55:41Z
• Authors: Chia-Chen Liu; Julie Prior; David Piwnica-Worms; Guojun Bu
• Keywords: 0301 basic medicine; Cell Survival; Proliferation; Down-Regulation; Breast Neoplasms; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; RNA, Small Interfering; LDL-Receptor Related Proteins; Cell Proliferation; Mesd; Tumor Suppressor Proteins; Gene silencing; Wnt signaling; Xenograft Model Antitumor Assays; Up-Regulation; 3. Good health; Gene Expression Regulation, Neoplastic; Wnt Proteins; Gene Knockdown Techniques; Low Density Lipoprotein Receptor-Related Protein-6; Tumorigenesis; Female; Molecular Chaperones; Signal Transduction

The Wnt/β-catenin signaling pathway is activated in breast cancer, a leading cause of cancer mortality in women. Because mutations in the key intracellular components of this pathway are rare, identifying the molecular mechanisms of aberrant Wnt activation in breast cancer is critical for development of pathway-targeted therapy. Here, we show that expression of the Wnt signaling coreceptor LRP6 is up-regulated in a subpopulation of human breast cancers. LRP6 silencing in breast cancer cells reduces Wnt signaling, cell proliferation, and in vivo tumor growth. In vivo administration of an LRP6 antagonist, Mesd, markedly suppressed growth of MMTV-Wnt1 tumors without causing undesirable side effects. These results demonstrate that Wnt activation at the cell surface contributes to breast cancer tumorigenesis. Together, our studies highlight LRP6 as a potential therapeutic target in breast cancer, and introduce Mesd as a promising antitumor agent for treating breast cancer subtypes with Wnt activation at the cell surface.