{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:40:46Z","timestamp":1790793646951,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and\/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+\/\u2212 who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+\/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+\/\u2212 iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1\u03b1, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+\/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+\/\u2212 iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+\/\u2212 iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+\/\u2212 iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer.<\/jats:p>","DOI":"10.3390\/ijms22031227","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T06:10:54Z","timestamp":1611727854000},"page":"1227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-7285","authenticated-orcid":false,"given":"Lucie","family":"Portier","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-2524","authenticated-orcid":false,"given":"Christophe","family":"Desterke","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Chaker","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noufissa","family":"Oudrhiri","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"},{"name":"Division of Hematology, APHP-Paris Sud University Hospitals, 94270 Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afag","family":"Asgarova","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Dkhissi","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, UMR1082, University of Poitiers, 86000 Poitiers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali G.","family":"Turhan","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"},{"name":"Division of Hematology, APHP-Paris Sud University Hospitals, 94270 Le Kremlin Bic\u00eatre, France"},{"name":"Faculty of Medecine, University Paris-Saclay, 94270 Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3557-4499","authenticated-orcid":false,"given":"Annelise","family":"Bennaceur-Griscelli","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"},{"name":"Division of Hematology, APHP-Paris Sud University Hospitals, 94270 Le Kremlin Bic\u00eatre, France"},{"name":"Faculty of Medecine, University Paris-Saclay, 94270 Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Griscelli","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\u2013UMR935\/UA9, University Paris-Saclay, 94800 Villejuif, France"},{"name":"INGESTEM, CITHERA, National IPSC Infrastructure, INSERM University Paris-Saclay, 94800 Villejuif, France"},{"name":"D\u00e9partement de Biologie M\u00e9dicale et Pathologie M\u00e9dicales, Service de microbiologie, Gustave Roussy Cancer Campus, 94805 Villejuif, France"},{"name":"Facult\u00e9 de la Sorbonne Paris Cit\u00e9, Facult\u00e9 des Sciences Pharmaceutiques et Biologiques, University of Paris, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1387\/ijdb.041802ad","article-title":"The stroma reaction myofibroblast: A key player in the control of tumor cell behavior","volume":"48","author":"Desmouliere","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1158\/0008-5472.CAN-10-0538","article-title":"Breast Cancer Stem Cells Are Regulated by Mesenchymal Stem Cells through Cytokine Networks","volume":"71","author":"Liu","year":"2011","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1172\/JCI45273","article-title":"Human ovarian carcinoma\u2013associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production","volume":"121","author":"McLean","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1093\/jnci\/djh299","article-title":"Mesenchymal Stem Cells: Potential Precursors for Tumor Stroma and Targeted-Delivery Vehicles for Anticancer Agents","volume":"96","author":"Studeny","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1002\/stem.187","article-title":"Direct Evidence of Mesenchymal Stem Cell Tropism for Tumor and Wounding Microenvironments Using In Vivo Bioluminescent Imaging","volume":"27","author":"Kidd","year":"2009","journal-title":"Stem Cells"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10549-011-1577-0","article-title":"Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF\/EGFR\/Akt pathway","volume":"132","author":"Yan","year":"2011","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms2766","article-title":"Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis","volume":"4","author":"Jung","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.stem.2014.10.001","article-title":"MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis","volume":"15","author":"Cuiffo","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature06188","article-title":"Mesenchymal stem cells within tumour stroma pro-mote breast cancer metastasis","volume":"449","author":"Karnoub","year":"2007","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10044","DOI":"10.1158\/0008-5472.CAN-10-1254","article-title":"Human bone marrow-derived MSCs can home to ortho-topic breast cancer tumors and promote bone metastasis","volume":"70","author":"Goldstein","year":"2010","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17460","DOI":"10.1073\/pnas.1206653109","article-title":"Critical Role for Lysyl Oxidase in Mesenchymal Stem Cell-Driven Breast Cancer Malignancy","volume":"109","author":"Bell","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","first-page":"189","article-title":"Hypoxia-inducible factor-dependent breast can-cer-mesenchymal stem cell bidirectional signaling promotes metastasis","volume":"12","author":"Chaturvedi","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/jcp.10257","article-title":"BRCA1 gene in breast cancer","volume":"196","author":"Rosen","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1093\/jnci\/djg050","article-title":"Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer","volume":"95","author":"Foulkes","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R47","DOI":"10.1186\/bcr2334","article-title":"Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes","volume":"11","author":"Stefansson","year":"2009","journal-title":"Breast Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1158\/1940-6207.CAPR-09-0078","article-title":"Altered Gene Expression in Morphologically Normal Epithelial Cells from Heterozygous Carriers of BRCA1 or BRCA2 Mutations","volume":"3","author":"Bellacosa","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1002\/gcc.20723","article-title":"Genomic alterations in histopathologically nor-mal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufciency","volume":"49","author":"Rennstam","year":"2010","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.scr.2017.09.003","article-title":"Generation of induced pluripotent stem cell (iPSC) line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene","volume":"24","author":"Griscelli","year":"2017","journal-title":"Stem Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1002\/humu.20723","article-title":"MLPA screening in theBRCA1gene from 1506 German hereditary breast cancer cases: Novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases","volume":"29","author":"Engert","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s002140050405","article-title":"Molecular modeling of the hypoxia-inducible factor-1 (HIF-1)","volume":"101","author":"Michel","year":"1999","journal-title":"Theor. Chem. Accounts"},{"key":"ref_22","first-page":"485","article-title":"Role of HIF-1\u03b1 in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis","volume":"394","author":"Carmeliet","year":"1998","journal-title":"Nat. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.4161\/cc.22316","article-title":"Downregulation of stromal BRCA1 drives breast cancer tumor growth via upregulation of HIF-1\u03b1, autophagy and ketone body production","volume":"11","author":"Salem","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1128\/MCB.01338-07","article-title":"Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis","volume":"28","author":"Guzy","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s10549-007-9817-z","article-title":"High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer","volume":"111","author":"Bouter","year":"2008","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/sj.bjc.6605287","article-title":"BRCA1 tumours correlate with a HIF-1alpha phe-notype and have a poor prognosis through modulation of hydroxylase enzyme profile expression","volume":"101","author":"Yan","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL tar-gets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4604","DOI":"10.1128\/MCB.16.9.4604","article-title":"Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1","volume":"16","author":"Forsythe","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00428-011-1151-5","article-title":"Periostin expression and epithelial-mesenchymal transition in cancer: A review and an update","volume":"459","author":"Morra","year":"2011","journal-title":"Virchows Arch."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/jcb.21224","article-title":"Periostin regulates collagen fi-brillogenesis and the biomechanical properties of connective tissues","volume":"101","author":"Norris","year":"2007","journal-title":"J. Cell Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1152\/japplphysiol.01311.2003","article-title":"Hypoxia-responsive growth factors upregulate periostin and osteopontin expression via distinct signaling pathways in rat pulmonary arterial smooth muscle cells","volume":"97","author":"Li","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S1535-6108(04)00081-9","article-title":"Periostin potently promotes metastatic growth of colon cancer by aug-menting cell survival via the Akt\/PKB pathway","volume":"5","author":"Bao","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_33","first-page":"5358","article-title":"Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility","volume":"62","author":"Gillan","year":"2002","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19700","DOI":"10.1074\/jbc.M601856200","article-title":"Transduction of a Mesenchyme-specific Gene Periostin into 293T Cells Induces Cell Invasive Activity through Epithelial-Mesenchymal Transformation","volume":"281","author":"Yan","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_35","first-page":"1759","article-title":"Opposite regulation of epithelial-to-mesenchymal transition and cell invasiveness by periostin between prostate and bladder cancer cells","volume":"38","author":"Inoue","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nrc822","article-title":"Epithelial\u2013mesenchymal transitions in tumour progression","volume":"2","author":"Thiery","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kaur, P., Nagaraja, G.M., Zheng, H., Gizachew, D., Galukande, M., Krishnan, S., and Asea, A. (2012). A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-120"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1158\/1541-7786.MCR-15-0079","article-title":"Tumor Cell-Derived Periostin Regu-lates Cytokines That Maintain Breast Cancer Stem Cells","volume":"14","author":"Lambert","year":"2016","journal-title":"Mol. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/path.4747","article-title":"Periostin promotes immunosuppressive premetastatic niche for-mation to facilitate breast tumour metastasis","volume":"239","author":"Wang","year":"2016","journal-title":"J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1158\/1078-0432.CCR-14-3111","article-title":"Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer","volume":"21","author":"Ryner","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kujawa, K.A., Zembala-No\u017cy\u0144ska, E., Cortez, A.J., Kujawa, T., Kupryja\u0144czyk, J., and Lisowska, K.M. (2020). Fibronectin and Periostin as Prognostic Markers in Ovarian Cancer. 1. Cells, 9.","DOI":"10.3390\/cells9010149"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1182\/blood-2010-12-325324","article-title":"Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery","volume":"118","author":"Giuliani","year":"2011","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1073\/pnas.091062498","article-title":"Significance analysis of microarrays applied to the ionizing radiation response","volume":"98","author":"Tusher","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","first-page":"1","article-title":"FactoMineR: An R Package for Multivariate Analysis","volume":"25","author":"Josse","year":"2008","journal-title":"J. Stat. Softw."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1093\/bioinformatics\/bts366","article-title":"GO-Elite: A flexible solution for pathway and ontology over-representation","volume":"28","author":"Zambon","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1038\/nprot.2007.324","article-title":"Integration of biological networks and gene expression data using Cytoscape","volume":"2","author":"Cline","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1111\/j.1582-4934.2008.00161.x","article-title":"Thrombin bound to a fibrin clot confers angiogenic and haemostatic properties on endothelial progenitor cells","volume":"12","author":"Smadja","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s10549-014-3118-0","article-title":"An improved syngeneic orthotopic murine model of human breast cancer progression","volume":"147","author":"Rashid","year":"2014","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1158\/1535-7163.MCT-14-0226","article-title":"Midkine Lacking Its Last 40 Amino Acids Acts on Endothelial and Neuroblastoma Tumor Cells and Inhibits Tumor Development","volume":"14","author":"Dianat","year":"2015","journal-title":"Mol. Cancer Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:15:55Z","timestamp":1760159755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,27]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031227"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031227","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,27]]}}}