‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin

Abu-Tayeh, Hanan; Weidenfeld, Keren; Zhilin-Roth, Alisa; Schif-Zuck, Sagie; Thaler, Sonja; Cotarelo, Cristina; Tan, Tuan Zea; Thiery, Jean Paul; Green, Jeffrey E.; Klorin, Geula; Sabo, Edmond; Sleeman, Jonathan; Tzukerman, Maty; Barkan, Dalit

doi:10.1038/cddis.2016.387

Cited by 16 publications

(16 citation statements)

References 52 publications

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“…The ECM influences organization ( 15 ) and differentiation ( 18 , 19 ) of mammary cells into functional mammary structures and tissues. It plays a role in tumor suppression through trafficking of intercellular signals ( 20 ) and exerting physical forces sensed by cell surface proteins, such as integrins ( 10 , 13 , 15 ). Changes in the ECM composition ( 15 , 18 , 19 , 21 ) and stiffness ( 6 – 8 , 15 , 22 , 23 ) have been shown to promote malignant phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Joyce

James

et al. 2018

Front. Oncol.

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The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.

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Section: Introductionmentioning

confidence: 99%

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Joyce

James

et al. 2018

Front. Oncol.

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“…Similar results have linked expression of alpha(v)beta(3) integrin (Int-αvβ3) to expression of malignant phenotypes in MCF7 ER + breast carcinoma cells [4]. Abu-Tayeh et al used basement membrane extract to generate 3D cultures of MCF7 cells and were able to measure malignancy based on acinar formation, apical-basal polarity, and presence/absence of a hollow lumen.…”

Section: Microenvironmental Control Of Tumorigenesis: a Role For Matrmentioning

confidence: 62%

Novel Nanomaterials Enable Biomimetic Models of the Tumor Microenvironment

Joyce

Allen

Suggs³

et al. 2017

Journal of Nanotechnology

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In the complex tumor microenvironment, chemical and mechanical signals from tumor cells, stromal cells, and the surrounding extracellular matrix in uence all aspects of disease progression and response to treatment. Modeling the physical properties of the tumor microenvironment has been a signi cant e ort in the biomaterials eld. One challenge has been the di culty in altering the mechanical properties of the extracellular matrix without simultaneously impacting other factors that in uence cell behavior. e development of novel materials based on nanotechnology has enabled recent innovations in tumor cell culture models. Here, we review the various approaches by which the tumor cell microenvironment has been engineered using natural and synthetic gels. We describe new studies that rely on the unique temporal and spatial control a orded by nanomaterials to produce culture platforms that mimic dynamic changes in tumor matrix mechanics. In addition, we look at the frontier of nanomaterial-hydrogel composites to review new approaches for perturbation of mechanochemical control in the tumor microenvironment.

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“…The genes were ranked by the frequency of enrichments in biological process. Of the top 10 genes in HMLncs, nine were demonstrated to be associated with BRCA: FOXJ1 [ 31 ], HDAC2 [ 32 ], WNT1 [ 33 ], SOX18 [ 34 ], NOTCH4 [ 35 ], SP3 [ 36 ], HOXA11 [ 37 ], HOXC11 [ 38 ] and FOXD3 [ 39 ]. In addition, there were six genes coding transcription factors in the top 10 genes ( FOXJ1 , SOX18 , SP3 , HOXA11 , HOXC11 and FOXD3 ) (Figure 3E ).…”

Section: Resultsmentioning

confidence: 99%

The landscape of DNA methylation-mediated regulation of long non-coding RNAs in breast cancer

Zhang

Wang

et al. 2017

Oncotarget

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Although systematic studies have identified a host of long non-coding RNAs (lncRNAs) which are involved in breast cancer, the knowledge about the methyla-tion-mediated dysregulation of those lncRNAs remains limited. Here, we integrated multi-omics data to analyze the methylated alteration of lncRNAs in breast invasive carcinoma (BRCA). We found that lncRNAs showed diverse methylation patterns on promoter regions in BRCA. LncRNAs were divided into two categories and four subcategories based on their promoter methylation patterns and expression levels be-tween tumor and normal samples. Through cis-regulatory analysis and gene ontology network, abnormally methylated lncRNAs were identified to be associated with can-cer regulation, proliferation or expression of transcription factors. Competing endog-enous RNA network and functional enrichment analysis of abnormally methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in several hallmarks and KEGG pathways of cancers significantly. Finally, survival analysis based on mRNA modules in networks revealed that lncRNAs silenced by high methylation were associated with prognosis significantly in BRCA. This study enhances the understanding of aberrantly methylated patterns of lncRNAs and pro-vides a novel insight for identifying cancer biomarkers and potential therapeutic tar-gets in breast cancer.

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‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin

Cited by 16 publications

References 52 publications

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Novel Nanomaterials Enable Biomimetic Models of the Tumor Microenvironment

The landscape of DNA methylation-mediated regulation of long non-coding RNAs in breast cancer

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