title: Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; the effect of pharmacological targeting TGFβ receptor I kinase.
abstract: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most frequently occurring histological subtypes of breast cancer, accounting for 80-90% and 10-15% 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 ILC model of spontaneous bone micrometastasis. We used murine invasive lobular breast carcinoma cells (KEP) that were generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1((F/F));Trp53((F/F)) mouse model of de novo mammary tumour formation. After surgical resection of the growing orthotopically implanted KEP cells, distant metastases were formed. In contrast to other orthotopic breast cancer models, KEP cells readily formed skeletal metastases with minimal lung involvement. Continuous treatment with SD-208 (60 mg/kg per day), an orally available TGFβ receptor I kinase inhibitor, increased the tumour growth at the primary site and increased the number of distant metastases. Furthermore, when SD-208 treatment was started after surgical resection of the orthotopic tumour, increased bone colonisation was also observed (versus vehicle). Both our in vitro and in vivo data show that SD-208 treatment reduced TGFβ signalling, inhibited apoptosis, and increased proliferation. In conclusion, we have demonstrated that orthotopic implantation of murine ILC cells represent a new breast cancer model of minimal residual disease in vivo, which comprises key steps of the metastatic cascade. The cancer cells are sensitive to the anti-tumour effects of TGFβ. Our in vivo 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.
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Jeroen T
authors.initials: JT
authors.lastname: Buijs
authors.forename: Kasia M
authors.initials: KM
authors.lastname: Matula
authors.forename: Henry
authors.initials: H
authors.lastname: Cheung
authors.forename: Marianna
authors.initials: M
authors.lastname: Kruithof-de Julio
authors.forename: Maaike H
authors.initials: MH
authors.lastname: van der Mark
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Snoeks
authors.forename: Ron
authors.initials: R
authors.lastname: Cohen
authors.forename: Willem E
authors.initials: WE
authors.lastname: Corver
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D064200:Cdh1 Proteins / Q000172:deficiency / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018345:Mice, Knockout; D061206:Neoplasm Micrometastasis; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000633:toxicity*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; C511004:SD-208; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: SD-208; TGFβ; breast cancer; invasive lobular carcinoma; metastasis; minimal residual disease; mouse model; receptor I kinase inhibitor