{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T11:12:30Z","timestamp":1772881950551,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Deutsches Krebsforschungszentrum (DKFZ)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Integrin \u03b23 (ITGB3) is probably related to skeletal metastasis, which is the most frequent complication in breast cancer progression. We aimed to define its role and suitability as target for anti-metastatic therapy. We generated two MDA-MB-231 cell clones with conditional miRNA-mediated ITGB3 knockdown for analyzing the resulting effects in vitro regarding mRNA expression, proliferation and migration, as well the impact on skeletal metastasis in a nude rat model. Furthermore, ITGB3 levels were analyzed in exosomes from plasma of rats with skeletal metastases, and from MDA-MB-231 cells incubated with these vesicles, as well as from exosomes secreted by cells with conditional ITGB3 knockdown. This inhibition of ITGB3 expression decreased cellular proliferation and more distinctly inhibited cellular migration. Reduction and even complete remissions of respective soft tissue and osteolytic lesions were detected after ITGB3 knockdown in vivo. Furthermore, ITGB3 levels were increased in exosomes isolated from plasma of rats harboring MDA-MB-231 lesions as well as in respective cells incubated with these vesicles in vitro. ITGB3 was distinctly decreased in exosomes from cells with ITGB3 knockdown. The observed in vitro and in vivo anti-ITGB3 effects can be explained by downregulation of specific genes, which have roles in angiogenesis (<jats:italic>NPTN, RRM2<\/jats:italic>), tumor growth (<jats:italic>NPTN<\/jats:italic>), energy metabolism (<jats:italic>ISCA1<\/jats:italic>), cytokinesis (<jats:italic>SEPT11<\/jats:italic>), migration (<jats:italic>RRM2, STX6<\/jats:italic>), cell proliferation, invasiveness, senescence, tumorigenesis (<jats:italic>RRM2<\/jats:italic>) and vesicle trafficking (<jats:italic>SEPT11, STX6<\/jats:italic>). ITGB3 has a role in breast cancer skeletal metastasis via gene expression modulation, as mirrored for ITGB3 in exosomes, thus it could serve as target for anti-metastatic therapy.<\/jats:p>","DOI":"10.1007\/s00432-020-03428-y","type":"journal-article","created":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T18:03:17Z","timestamp":1603216997000},"page":"361-371","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Conditional knockdown of integrin beta-3 reveals its involvement in osteolytic and soft tissue lesions of breast cancer skeletal metastasis"],"prefix":"10.1007","volume":"147","author":[{"given":"Marineta","family":"Kovacheva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Zepp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Berger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3783-5365","authenticated-orcid":false,"given":"Martin R.","family":"Berger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,20]]},"reference":[{"issue":"10","key":"3428_CR1","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1002\/ijc.25563","volume":"128","author":"T Bauerle","year":"2011","unstructured":"Bauerle T, Komljenovic D, Merz M, Berger MR, Goodman SL, Semmler W (2011) Cilengitide inhibits progression of experimental breast cancer bone metastases as imaged noninvasively using VCT, MRI and DCE-MRI in a longitudinal in vivo study. Int J Cancer 128(10):2453\u20132462. https:\/\/doi.org\/10.1002\/ijc.25563","journal-title":"Int J Cancer"},{"issue":"2","key":"3428_CR2","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1002\/ijc.27675","volume":"132","author":"F Castro","year":"2013","unstructured":"Castro F, Dirks WG, Fahnrich S, Hotz-Wagenblatt A, Pawlita M, Schmitt M (2013) High-throughput SNP-based authentication of human cell lines. Int J Cancer 132(2):308\u2013314. https:\/\/doi.org\/10.1002\/ijc.27675","journal-title":"Int J Cancer"},{"key":"3428_CR3","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20182062","author":"WX Chen","year":"2019","unstructured":"Chen WX, Yang LG, Xu LY, Cheng L, Qian Q, Sun L, Zhu YL (2019) Bioinformatics analysis revealing prognostic significance of RRM2 gene in breast cancer. Biosci Rep. https:\/\/doi.org\/10.1042\/BSR20182062","journal-title":"Biosci Rep"},{"issue":"2","key":"3428_CR4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.bbapap.2004.05.004","volume":"1700","author":"I Cozar-Castellano","year":"2004","unstructured":"Cozar-Castellano I, del Valle MM, Trujillo E, Arteaga MF, Gonzalez T, Martin-Vasallo P, Avila J (2004) hIscA: a protein implicated in the biogenesis of iron-sulfur clusters. Biochem Biophys Acta 1700(2):179\u2013188. https:\/\/doi.org\/10.1016\/j.bbapap.2004.05.004","journal-title":"Biochem Biophys Acta"},{"issue":"1","key":"3428_CR5","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1002\/jcp.25821","volume":"233","author":"V Das","year":"2018","unstructured":"Das V, Kalyan G, Hazra S, Pal M (2018) Understanding the role of structural integrity and differential expression of integrin profiling to identify potential therapeutic targets in breast cancer. J Cell Physiol 233(1):168\u2013185. https:\/\/doi.org\/10.1002\/jcp.25821","journal-title":"J Cell Physiol"},{"issue":"1","key":"3428_CR6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrc2748","volume":"10","author":"JS Desgrosellier","year":"2010","unstructured":"Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10(1):9\u201322. https:\/\/doi.org\/10.1038\/nrc2748","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"3428_CR7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.4161\/cbt.12.1.15719","volume":"12","author":"RB Georges","year":"2011","unstructured":"Georges RB, Adwan H, Hamdi H, Hielscher T, Linnemann U, Berger MR (2011) The insulin-like growth factor binding proteins 3 and 7 are associated with colorectal cancer and liver metastasis. Cancer Biol Ther 12(1):69\u201379. https:\/\/doi.org\/10.4161\/cbt.12.1.15719","journal-title":"Cancer Biol Ther"},{"issue":"9","key":"3428_CR8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41568-018-0038-z","volume":"18","author":"H Hamidi","year":"2018","unstructured":"Hamidi H, Ivaska J (2018) Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer 18(9):533\u2013548. https:\/\/doi.org\/10.1038\/s41568-018-0038-z","journal-title":"Nat Rev Cancer"},{"issue":"9","key":"3428_CR9","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/bjc.2016.312","volume":"115","author":"H Hamidi","year":"2016","unstructured":"Hamidi H, Pietila M, Ivaska J (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer 115(9):1017\u20131023. https:\/\/doi.org\/10.1038\/bjc.2016.312","journal-title":"Br J Cancer"},{"issue":"1\u20133","key":"3428_CR10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.febslet.2004.05.030","volume":"568","author":"N Hanai","year":"2004","unstructured":"Hanai N, Nagata K, Kawajiri A, Shiromizu T, Saitoh N, Hasegawa Y, Murakami S, Inagaki M (2004) Biochemical and cell biological characterization of a mammalian septin, Sept11. FEBS Lett 568(1\u20133):83\u201388. https:\/\/doi.org\/10.1016\/j.febslet.2004.05.030","journal-title":"FEBS Lett"},{"issue":"7578","key":"3428_CR11","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nature15756","volume":"527","author":"A Hoshino","year":"2015","unstructured":"Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527(7578):329\u2013335. https:\/\/doi.org\/10.1038\/nature15756","journal-title":"Nature"},{"issue":"12","key":"3428_CR12","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1093\/jnci\/djh169","volume":"96","author":"A Karadag","year":"2004","unstructured":"Karadag A, Ogbureke KU, Fedarko NS, Fisher LW (2004) Bone sialoprotein, matrix metalloproteinase 2, and alpha(v)beta3 integrin in osteotropic cancer cell invasion. J Natl Cancer Inst 96(12):956\u2013965. https:\/\/doi.org\/10.1093\/jnci\/djh169","journal-title":"J Natl Cancer Inst"},{"issue":"14","key":"3428_CR13","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.18632\/oncotarget.2132","volume":"5","author":"M Kovacheva","year":"2014","unstructured":"Kovacheva M, Zepp M, Berger SM, Berger MR (2014) Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis. Oncotarget 5(14):5510\u20135522. https:\/\/doi.org\/10.18632\/oncotarget.2132","journal-title":"Oncotarget"},{"key":"3428_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20194918","author":"M Kovacheva","year":"2019","unstructured":"Kovacheva M, Zepp M, Schraad M, Berger S, Berger MR (2019) Conditional knockdown of osteopontin inhibits breast cancer skeletal metastasis. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms20194918","journal-title":"Int J Mol Sci"},{"issue":"7","key":"3428_CR15","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1007\/s11033-010-0009-2","volume":"37","author":"M Liu","year":"2010","unstructured":"Liu M, Shen S, Chen F, Yu W, Yu L (2010) Linking the septin expression with carcinogenesis. Mol Biol Rep 37(7):3601\u20133608. https:\/\/doi.org\/10.1007\/s11033-010-0009-2","journal-title":"Mol Biol Rep"},{"issue":"1","key":"3428_CR16","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1186\/s40064-016-2502-0","volume":"5","author":"L Pan","year":"2016","unstructured":"Pan L, Zhao Y, Yuan Z, Qin G (2016) Research advances on structure and biological functions of integrins. SpringerPlus 5(1):1094. https:\/\/doi.org\/10.1186\/s40064-016-2502-0","journal-title":"SpringerPlus"},{"issue":"5","key":"3428_CR17","doi-asserted-by":"publisher","first-page":"e33788","DOI":"10.1371\/journal.pone.0033788","volume":"7","author":"AA Powell","year":"2012","unstructured":"Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, Telli ML, Advani RH, Carlson RW, Mollick JA, Sheth S, Kurian AW, Ford JM, Stockdale FE, Quake SR, Pease RF, Mindrinos MN, Bhanot G, Dairkee SH, Davis RW, Jeffrey SS (2012) Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS ONE 7(5):e33788. https:\/\/doi.org\/10.1371\/journal.pone.0033788","journal-title":"PLoS ONE"},{"key":"3428_CR18","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29225","author":"D Quan","year":"2019","unstructured":"Quan D, Chen K, Zhang J, Guan Y, Yang D, Wu H, Wu S, Lv L (2019) Identification of lncRNA NEAT1\/miR-21\/RRM2 axis as a novel biomarker in breast cancer. J Cell Physiol. https:\/\/doi.org\/10.1002\/jcp.29225","journal-title":"J Cell Physiol"},{"key":"3428_CR19","doi-asserted-by":"publisher","DOI":"10.3390\/cancers9090110","author":"S Raab-Westphal","year":"2017","unstructured":"Raab-Westphal S, Marshall JF, Goodman SL (2017) Integrins as therapeutic targets: successes and cancers. Cancers. https:\/\/doi.org\/10.3390\/cancers9090110","journal-title":"Cancers"},{"issue":"5","key":"3428_CR20","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s10585-012-9462-8","volume":"29","author":"C Reufsteck","year":"2012","unstructured":"Reufsteck C, Lifshitz-Shovali R, Zepp M, Bauerle T, Kubler D, Golomb G, Berger MR (2012) Silencing of skeletal metastasis-associated genes impairs migration of breast cancer cells and reduces osteolytic bone lesions. Clin Exp Metas 29(5):441\u2013456. https:\/\/doi.org\/10.1007\/s10585-012-9462-8","journal-title":"Clin Exp Metas"},{"issue":"2","key":"3428_CR21","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s00262-008-0543-0","volume":"58","author":"D Rodriguez-Pinto","year":"2009","unstructured":"Rodriguez-Pinto D, Sparkowski J, Keough MP, Phoenix KN, Vumbaca F, Han DK, Gundelfinger ED, Beesley P, Claffey KP (2009) Identification of novel tumor antigens with patient-derived immune-selected antibodies. Cancer Immunol Immunother CII 58(2):221\u2013234. https:\/\/doi.org\/10.1007\/s00262-008-0543-0","journal-title":"Cancer Immunol Immunother CII"},{"issue":"16","key":"3428_CR22","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1056\/NEJMra030831","volume":"350","author":"GD Roodman","year":"2004","unstructured":"Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350(16):1655\u20131664. https:\/\/doi.org\/10.1056\/NEJMra030831","journal-title":"N Engl J Med"},{"issue":"2","key":"3428_CR23","doi-asserted-by":"publisher","first-page":"115","DOI":"10.4103\/0973-1482.82912","volume":"7","author":"M Uccello","year":"2011","unstructured":"Uccello M, Malaguarnera G, Vacante M, Motta M (2011) Serum bone sialoprotein levels and bone metastases. J Cancer Res Ther 7(2):115\u2013119. https:\/\/doi.org\/10.4103\/0973-1482.82912","journal-title":"J Cancer Res Ther"},{"issue":"6","key":"3428_CR24","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nrc3055","volume":"11","author":"KN Weilbaecher","year":"2011","unstructured":"Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11(6):411\u2013425. https:\/\/doi.org\/10.1038\/nrc3055","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"3428_CR25","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1002\/ame2.12059","volume":"2","author":"X Yang","year":"2019","unstructured":"Yang X, Lu D, Zhang X, Chen W, Gao S, Dong W, Ma Y, Zhang L (2019) Knockout of ISCA1 causes early embryonic death in rats. Anim Models Exp Med 2(1):18\u201324. https:\/\/doi.org\/10.1002\/ame2.12059","journal-title":"Anim Models Exp Med"},{"issue":"6","key":"3428_CR26","doi-asserted-by":"publisher","first-page":"930","DOI":"10.4161\/cbt.6.6.4188","volume":"6","author":"DY Yosifov","year":"2007","unstructured":"Yosifov DY, Dineva IK, Zaharieva MM, Konstantinov SM, Berger MR (2007) The expression level of the tumor suppressor retinoblastoma protein (Rb) influences the antileukemic efficacy of erucylphospho-N, N, N-trimethylpropylammonium (ErPC3). Cancer Biol Ther 6(6):930\u2013935. https:\/\/doi.org\/10.4161\/cbt.6.6.4188","journal-title":"Cancer Biol Ther"},{"key":"3428_CR27","first-page":"453","volume-title":"Breast cancer\u2014current and alternative therapeutic modalities","author":"M Zepp","year":"2011","unstructured":"Zepp M, Baeuerle T, Elazar V, Peterschmitt J, Lifshitz-Shovali R, Adwan H, Armbruster FP, Golomb G, Berger MR (2011) Treatment of breast cancer lytic skeletal metastasis using a model in nude rats. In: Gunduz E, Gunduz M (eds) Breast cancer\u2014current and alternative therapeutic modalities. InTech Open Access Publisher, Rijeka, pp 453\u2013488"},{"issue":"22","key":"3428_CR28","doi-asserted-by":"publisher","first-page":"4238","DOI":"10.1242\/jcs.191684","volume":"129","author":"L Zhu","year":"2016","unstructured":"Zhu L, Xiong X, Kim Y, Okada N, Lu F, Zhang H, Sun H (2016) Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells. J Cell Sci 129(22):4238\u20134251. https:\/\/doi.org\/10.1242\/jcs.191684","journal-title":"J Cell Sci"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-020-03428-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-020-03428-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-020-03428-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T12:13:39Z","timestamp":1634732019000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-020-03428-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,20]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["3428"],"URL":"https:\/\/doi.org\/10.1007\/s00432-020-03428-y","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,20]]},"assertion":[{"value":"18 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The animal experiments were performed in accordance with the commonly accepted \u201c3Rs\u201d (i.e., replacement of animals by alternatives wherever possible, reduction in the number of animals used, and refinement of the experimental conditions and procedures to minimize the harm to animals) and according to national and international guidelines, and has been approved by the authors\u2019 institutional review board. All animal experiments were approved by the responsible governmental animal ethics committee (Regierungspr\u00e4sidium Karlsruhe, Germany, 35-9185.81-G70\/12).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}