{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:43:39Z","timestamp":1781250219425,"version":"3.54.1"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,1,23]],"date-time":"2015-01-23T00:00:00Z","timestamp":1421971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Netherlands Organisation for Scientific Research","doi-asserted-by":"crossref","award":["916.131.10"],"award-info":[{"award-number":["916.131.10"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Invasive ductal carcinoma (<jats:styled-content style=\"fixed-case\">IDC<\/jats:styled-content>) and invasive lobular carcinoma (<jats:styled-content style=\"fixed-case\">ILC<\/jats:styled-content>) are the most frequently occurring histological subtypes of breast cancer, accounting for 80\u201390% and 10\u201315% of the total cases, respectively. At the time of diagnosis and surgical resection of the primary tumour, most patients do not have clinical signs of metastases, but bone micrometastases may already be present. Our aim was to develop a novel preclinical <jats:styled-content style=\"fixed-case\">ILC<\/jats:styled-content> model of spontaneous bone micrometastasis. We used murine invasive lobular breast carcinoma cells (<jats:styled-content style=\"fixed-case\">KEP<\/jats:styled-content>) that were generated by targeted deletion of E\u2010cadherin and p53 in a conditional <jats:italic>K14cre;Cdh1<\/jats:italic>(<jats:sup><jats:italic>F\/F<\/jats:italic><\/jats:sup>);<jats:italic>Trp53<\/jats:italic>(<jats:sup><jats:italic>F\/F<\/jats:italic><\/jats:sup>) mouse model of <jats:italic>de novo<\/jats:italic> mammary tumour formation. After surgical resection of the growing orthotopically implanted <jats:styled-content style=\"fixed-case\">KEP<\/jats:styled-content> cells, distant metastases were formed. In contrast to other orthotopic breast cancer models, <jats:styled-content style=\"fixed-case\">KEP<\/jats:styled-content> cells readily formed skeletal metastases with minimal lung involvement. Continuous treatment with <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>\u2010208 (60\u2009mg\/kg per day), an orally available <jats:styled-content style=\"fixed-case\">TGF\u03b2<\/jats:styled-content> receptor I kinase inhibitor, increased the tumour growth at the primary site and increased the number of distant metastases. Furthermore, when <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>\u2010208 treatment was started after surgical resection of the orthotopic tumour, increased bone colonisation was also observed (versus vehicle). Both our <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> data show that <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>\u2010208 treatment reduced <jats:styled-content style=\"fixed-case\">TGF\u03b2<\/jats:styled-content> signalling, inhibited apoptosis, and increased proliferation. In conclusion, we have demonstrated that orthotopic implantation of murine <jats:styled-content style=\"fixed-case\">ILC<\/jats:styled-content> cells represent a new breast cancer model of minimal residual disease <jats:italic>in vivo<\/jats:italic>, which comprises key steps of the metastatic cascade. The cancer cells are sensitive to the anti\u2010tumour effects of <jats:styled-content style=\"fixed-case\">TGF\u03b2<\/jats:styled-content>. Our <jats:italic>in vivo<\/jats:italic> model is ideally suited for functional studies and evaluation of new pharmacological intervention strategies that may target one or more steps along the metastatic cascade of events. \u00a9 2014 The Authors. The Journal of Pathology published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4488","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T04:11:36Z","timestamp":1416888696000},"page":"745-759","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; the effect of pharmacological targeting TGF\u03b2 receptor I kinase"],"prefix":"10.1002","volume":"235","author":[{"given":"Jeroen T","family":"Buijs","sequence":"first","affiliation":[{"name":"Department of Urology Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasia M","family":"Matula","sequence":"additional","affiliation":[{"name":"Department of Urology Leiden University Medical Centre  Leiden 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