title: FH535 inhibited migration and growth of breast cancer cells.
abstract: There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.
authors.affiliation: Department of Cell Biology, Windber Research Institute, Windber, Pennsylvania, United States of America. g.iida@wriwindber.org
authors.forename: Joji
authors.initials: J
authors.lastname: Iida
authors.forename: Jesse
authors.initials: J
authors.lastname: Dorchak
authors.forename: John R
authors.initials: JR
authors.lastname: Lehman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Clancy
authors.forename: Chunqing
authors.initials: C
authors.lastname: Luo
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Chen
authors.forename: Stella
authors.initials: S
authors.lastname: Somiari
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Ellsworth
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Mural
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; D010750:Phosphoproteins; D013449:Sulfonamides; D051153:Wnt Proteins; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C575430:FH535; C099942:NEDD9 protein, human