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      FH535 Inhibited Migration and Growth of Breast Cancer Cells

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          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.

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          β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation.

          Aberrant β-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of β-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of β-catenin expression in invasive breast cancers, the correlations between β-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant β-catenin expression is driven by CTNNB1 (β-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-β-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two β-catenin antibodies was observed (Spearman's r >0.62, P<0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of β-catenin membranous expression and nuclear accumulation. Complete lack of β-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of β-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between β-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, β-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, β-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer.
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            ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix

            Breast epithelial cells differentiate into tubules when cultured in floating three-dimensional (3D) collagen gels, but not when the cells are cultured in the same collagen matrix that is attached to the culture dish. These observations suggest that the biophysical properties of collagenous matrices regulate epithelial differentiation, but the mechanism by which this occurs is unknown. Tubulogenesis required the contraction of floating collagen gels through Rho and ROCK-mediated contractility. ROCK-mediated contractility diminished Rho activity in a floating 3D collagen gel, and corresponded to a loss of FAK phosphorylated at Y397 localized to 3D matrix adhesions. Increasing the density of floating 3D collagen gels also disrupted tubulogenesis, promoted FAK phosphorylation, and sustained high Rho activity. These data demonstrate the novel finding that breast epithelial cells sense the rigidity or density of their environment via ROCK-mediated contractility and a subsequent down-regulation of Rho and FAK function, which is necessary for breast epithelial tubulogenesis to occur.
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              Integrin signalling adaptors: not only figurants in the cancer story.

              Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects that are regulated by these adaptors in tumours might be crucial for the identification of new targets and the development of innovative therapeutic strategies for human cancer. In this Review we discuss the relevance of adaptor proteins in signalling that originates from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation in the context of cell transformation and tumour progression. We specifically underline the contribution of p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK and the integrin-linked kinase (ILK)-pinch-parvin (IPP) complex to cancer, along with the more recently identified p140 Cas-associated protein (p140CAP; also known as SRCIN1).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                11 September 2012
                : 7
                : 9
                : e44418
                Affiliations
                [1 ]Department of Cell Biology, Windber Research Institute, Windber, Pennsylvania, United States of America
                [2 ]Department of Biomedical Informatics, Windber Research Institute, Windber, Pennsylvania, United States of America
                [3 ]Department of Tissue Bank, Windber Research Institute, Windber, Pennsylvania, United States of America
                [4 ]Department of Genetics, Windber Research Institute, Windber, Pennsylvania, United States of America
                [5 ]Windber Research Institute, Windber, Pennsylvania, United States of America
                [6 ]Department of Surgery, Walter-Reed National Military Medical Center, Bethesda, Maryland, United States of America
                National Cancer Center, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JI. Performed the experiments: JRL RC JD. Analyzed the data: JI RE SS CL YC HH. Wrote the paper: JI. Critical discussion and revising the draft: RJM CDS.

                Article
                PONE-D-11-18703
                10.1371/journal.pone.0044418
                3439405
                22984505
                2ffa0dfc-5108-4a0b-94f6-f2ca588fc612
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 September 2011
                : 6 August 2012
                Page count
                Pages: 11
                Funding
                This research was supported by a grant from the United States Department of Defense (Military Molecular Medicine Initiative MDA W81XWHH-05-2-0075, Protocol 01-20006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Drug Discovery
                Biotechnology
                Drug Discovery
                Molecular Cell Biology
                Signal Transduction
                Signaling in Cellular Processes
                Beta-Catenin Signaling
                Signaling Pathways
                Catenin Signal Transduction
                Medicine
                Drugs and Devices
                Drug Research and Development
                Drug Discovery
                Obstetrics and Gynecology
                Breast Cancer
                Oncology
                Cancers and Neoplasms
                Breast Tumors
                Basic Cancer Research

                Uncategorized
                Uncategorized

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