{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:14:38Z","timestamp":1783606478553,"version":"3.55.0"},"reference-count":19,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Early placenta insulin-like growth factor (EPIL) is expressed by a subpopulation of the Her2-positive SKBR3 breast cancer cell line displaying high motility and transendothelial invasiveness in vitro, as recently shown by our group. As a consequence of this, we established cellular models by generating an EPIL-overexpressing SKBR3 cell line, knocked down EPIL by adding specific small interfering RNA (siRNA) to those cells and produced EPIL-enriched and depleted serum-free culture media. EPIL-expressing cells as well as EPIL-induced SKBR3 cells acquired a high capacity for transendothelial invasiveness. We observed a thin and outspread morphology caused by enhanced formation of lamellipodia, i.e. protrusions in the initial phase of motility. In parallel, Her2-positive MDAHer2 breast cancer cells also showed increased invasiveness when induced by EPIL-conditioned medium. A downstream signaling impact of EPIL could be observed in the form of reduced phosphorylation of Her2, erk1\/2 and akt, while phospholipase C\u03b31 phophorylation remained unaffected. As an in vivo model for highly motile tumor cells, Paget\u2019s disease of the nipple showed simultaneous EPIL and Her2 expression upon immunohistochemical examination using specific antibodies. Such experimental data have been translated to a clinical setting by using a prognostic tissue microarray established from 603 breast cancer cases. Survival data analysis found a significant association between expression levels of EPIL and 5-year overall survival that was dose dependent: EPIL (negative) 84%, EPIL (moderately positive) 77%, EPIL (strongly positive) 48% (P&amp;lt;0.005). One particular subgroup (7.6% of the cases with full clinical records) that comprised tumors simultaneously expressing EPIL and Her2 represented patients with the poorest 5-year overall survival. The results suggested that EPIL might be a cancer cell-produced growth factor that influences lateral Her2 signaling. Moreover, EPIL may be induced by factors apart from Her2 and may independently provide signaling for cancer invasion and motility.<\/jats:p>","DOI":"10.1677\/erc.1.00975","type":"journal-article","created":{"date-parts":[[2005,12,1]],"date-time":"2005-12-01T14:06:49Z","timestamp":1133446009000},"page":"823-837","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":21,"title":["Expression of early placenta insulin-like growth factor in breast cancer cells provides an autocrine loop that predominantly enhances invasiveness and motility"],"prefix":"10.1530","volume":"12","author":[{"given":"B","family":"Brandt","sequence":"first","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Kemming","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Packeisen","sequence":"additional","affiliation":[{"name":"1Institute of Pathology, University of Mu\u0308nster, Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Simon","sequence":"additional","affiliation":[{"name":"4Institute of Pathology, University of Basle, Basle, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Helms","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U","family":"Feldmann","sequence":"additional","affiliation":[{"name":"1Institute of Pathology, University of Mu\u0308nster, Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Matuschek","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Kersting","sequence":"additional","affiliation":[{"name":"1Institute of Pathology, University of Mu\u0308nster, Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Hinrichs","sequence":"additional","affiliation":[{"name":"2Institute of Pathology, Institute of Pathology, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-M","family":"Bidart","sequence":"additional","affiliation":[{"name":"2Institute of Pathology, Institute of Pathology, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Bellet","sequence":"additional","affiliation":[{"name":"3Departement de Biologie Clinique, Institut Gustave-Roussy Villejuif and Faculte\u0301 des Sciences Pharmaceutiques et Biologiques de Paris, FRE2443 CNRS, Universite\u0301 Rene\u0301 Decartes, Paris 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Bartkowiak","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Dankbar","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology, University Medical Center, Martinister. 52, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Dittmar","sequence":"additional","affiliation":[{"name":"5Institute of Immunology, University of Witten\/Herdecke, Witten, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Sauter","sequence":"additional","affiliation":[{"name":"4Institute of Pathology, University of Basle, Basle, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Boecker","sequence":"additional","affiliation":[{"name":"1Institute of Pathology, University of Mu\u0308nster, Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Buerger","sequence":"additional","affiliation":[{"name":"1Institute of Pathology, University of Mu\u0308nster, Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2026070909194342700_BALANA-ETAL-2001","doi-asserted-by":"crossref","unstructured":"Balana\n              ME\n            \n          , Labriola L, Salatino M, Movsichoff F, Peters G, Charreau EH& Elizade PV 2001 Activation of erbB-2 via hierarchical interaction between erbB-2 and type I insulin-like growth factor receptor in mammary tumor cells. Oncogene203434\u20133447.","DOI":"10.1038\/sj.onc.1204050"},{"key":"2026070909194342700_BELLET-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Bellet\n              D\n            \n          , Lavaissiere L, Mock P, Laurent A, Sabourin JC, Bedossa P, Le Bouteiller P, Frydman R, Troalen F& Bidart JM 1997 Identification of pro-EPIL and EPIL peptides translated from insulin-like 4 (INSL4) mRNA in human placenta. Journal of Clinical Endocrinology and Metabolism823169\u20133172.","DOI":"10.1210\/jcem.82.9.4359"},{"key":"2026070909194342700_BRANDT-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Brandt\n              B\n            \n          , Roetger A, Dittmar T, Nikolai G, Merschjann A, Nofer J-R, Assmann G & Zaenker KS 1999 c-erbB-2\/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. FASEB Journal131939\u20131949.","DOI":"10.1096\/fasebj.13.14.1939"},{"key":"2026070909194342700_BRANDT-ETAL-2002","unstructured":"Brandt\n              B\n            \n          , Roetger A, Bidart J-M, Packeisen J, Schier K, Mikesch J-H, Kemming D, Boecker W, Yu D & Buerger H 2002 Early placenta insulin like growth factor (pro-EPIL) is overexpressed and secreted by c-erbB-2 positive cells with high invasion potential. Cancer Research621020\u20131024."},{"key":"2026070909194342700_CHASSIN-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Chassin\n              D\n            \n          , Laurent A, Janneau JL, Berger R & Bellet D 1995 Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta. Genomics29465\u2013470.","DOI":"10.1006\/geno.1995.9980"},{"key":"2026070909194342700_DE-POTTER-AND-SCHELFHOUT-1995","unstructured":"De Potter\n              CR\n            \n           & Schelfhout AM 1995 The neu-protein and breast cancer. Virchows Archiv426107\u2013115."},{"key":"2026070909194342700_DITTMAR-ETAL-2002","doi-asserted-by":"crossref","unstructured":"Dittmar\n              T\n            \n          , Husemann A, Schewe Y, Nofer J-R, Niggemann B, Za\u0308nker KS & Brandt BH 2002 Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. FASEB Journal161823\u20131825.","DOI":"10.1096\/fj.02-0096fje"},{"key":"2026070909194342700_GILMORE-ETAL-2002","doi-asserted-by":"crossref","unstructured":"Gilmore\n              AP\n            \n          , Valentijn AJ, Wang P, Ranger AM, Bundred N, O\u2019Hare MJ, Wakeling A, Korsmeyer SJ & Streuli CH 2002 Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. Journal of Biological Chemistry27727643\u201327650.","DOI":"10.1074\/jbc.M108863200"},{"key":"2026070909194342700_GRAUS-PORTA-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Graus-Porta\n              D\n            \n          , Beerli RR, Daly JM & Hynes NE 1997 ErbB-2, the preferred heterodimerization partner of all erbB receptors, is a mediator of lateral signaling. EMBO Journal161647\u20131655.","DOI":"10.1093\/emboj\/16.7.1647"},{"key":"2026070909194342700_GUIDI-ETAL-2001","doi-asserted-by":"crossref","unstructured":"Guidi\n              A\n            \n          , Laricchia-Robbio L, Gianfaldoni D, Revoltella R & Del Bono G 2001 Comparison of a conventional immunoassay (ELISA) with a surface plasmon resonance-based biosensor for IGF-1 detection in cows\u2019 milk. Biosensors and Bioelectronics16971\u2013977.","DOI":"10.1016\/S0956-5663(01)00245-7"},{"key":"2026070909194342700_HOMBACH-KLONISCH-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Hombach-Klonisch\n              S\n            \n          , Buchmann J, Sarun S, Fischer B & Klonisch T 2000 Relaxin-like factor (RLF) is differentially expressed in the normal and neoplastic human mammary gland. Cancer892161\u20132168.","DOI":"10.1002\/1097-0142(20001201)89:11<2161::AID-CNCR3>3.3.CO;2-B"},{"key":"2026070909194342700_IRVINE-AND-SCHELL-2001","unstructured":"Irvine\n              RF\n            \n           & Schell MJ 2001 Back in the water: the return of the inositol phosphates. Nature Reviews in Molecular and Cellular Biology2327\u2013338."},{"key":"2026070909194342700_KATTERLE-ETAL-2004","unstructured":"Katterle\n              Y\n            \n          , Brandt BH, Dowdy SF, Niggemann B, Za\u0308nker KS & Dittmar T 2004 Effective inhibition of EGF induced cell migration of EGFR\/c-erbB-2 positive breast cancer cells using a recombinant PLC-\u03b31-(SH2)2-TAT protein. British Journal of Cancer90230\u2013235."},{"key":"2026070909194342700_MANN-ETAL-2004","doi-asserted-by":"crossref","unstructured":"Mann\n              CJ\n            \n          , Stephens SK & Burke JF 2004 Production of protein microarrays. In Protein Microarray Technology. Ed. D Kambhampati. Wiley-VCH.","DOI":"10.1002\/3527601554.ch8"},{"key":"2026070909194342700_MOCK-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Mock\n              P\n            \n          , Frydman R, Bellet D, Diawara DA, Lavaissiere L, Troalen F & Bidart JM 1999 Pro-EPIL forms are present in amniotic fluid and maternal serum during normal pregnancy. Journal of Clinical Endocrinology and Metabolism842253\u20132256.","DOI":"10.1210\/jcem.84.6.5888"},{"key":"2026070909194342700_RASMUSSEN-AND-CULLEN-1998","doi-asserted-by":"crossref","unstructured":"Rasmussen\n              AA\n            \n           & Cullen KJ 1998 Paracrine\/autocrine regulation of breast cancer by insulin-like growth factors. Breast Cancer Research and Treatment47219\u2013233.","DOI":"10.1023\/A:1005903000777"},{"key":"2026070909194342700_ROETGER-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Roetger\n              A\n            \n          , Merschjann A, Dittmar T, Jackisch C, Barnekow A & Brandt B 1998 Selection of potentially metastatic subpopulations expressing c-erbB-2 from breast cancer tissue by use of an extravasation model. American Journal of Pathology153697\u20131860.","DOI":"10.1016\/S0002-9440(10)65694-5"},{"key":"2026070909194342700_ROUNDABUSH-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Roundabush\n              FL\n            \n          , Pierce KL, Maudsley S, Khan DK & Luttrell LM 2000 Transactivation of the EGF receptor mediates IGF-1-stimulated Shc phosphorylation and erk1\/2 activation in COS-7 cells. Journal of Biological Chemistry27522583\u201322589.","DOI":"10.1074\/jbc.M002915200"},{"key":"2026070909194342700_SCHELFHOUT-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Schelfhout\n              VR\n            \n          , Coene ED, Delaey B, Thys S, Page DL & De Potter CR 2000 Pathogenesis of Paget\u2019s disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. Journal of the National Cancer Institute92622\u2013628.","DOI":"10.1093\/jnci\/92.8.622"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/12\/4\/0120823.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/12\/4\/823\/192389\/0120823.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/12\/4\/823\/192389\/0120823.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:19:50Z","timestamp":1783603190000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/12\/4\/823\/34522\/Expression-of-early-placenta-insulin-like-growth"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,12,1]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2005,12,1]]}},"URL":"https:\/\/doi.org\/10.1677\/erc.1.00975","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2005,12,1]]}}}