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.
Highlights
Triple negative (TN) breast cancers are defined by lack of expression of estrogen, progesterone, and HER-2 (ERBB2) receptors
We utilized MDA-MB-231 and HCC38 cells to evaluate the canonical WNT-signaling pathway in triple negative (TN) breast cancers since this pathway is activated evaluated by LRP6 expression [26], suggesting that the WNTsignaling pathway is activated in these cell lines
In a three-dimensional collagen matrix, which is considered as a model system for evaluating cancer growth in vivo, FH535 selectively inhibited TN breast cancer cell lines (i.e. HCC38 and MDA-MB-231) but not breast cancer cell lines from other subtypes (i.e. SK-Br3, T47D, and MCF-7)
Summary
Triple negative (TN) breast cancers are defined by lack of expression of estrogen, progesterone, and HER-2 (ERBB2) receptors. Recent studies analyzing gene expression profiles suggest that specific classes of TN breast cancer cells express genes regulating tumor migration, invasion, and differentiation, including TGF-b signaling pathways, extracellular matrix (ECM) reorganization, and the WNT-signaling pathway [5]. Consistent with this notion, immunohistochemical studies demonstrated that the canonical WNT-signaling pathway is activated in TN breast cancer cells compared to cells other of other molecular subtypes [6,7]. It is important for generating therapeutic strategies by evaluating how signaling pathways regulate tumor migration and invasion in TN breast cancer cells
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