Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; The effect of pharmacological targeting TGFβ receptor i kinase

Jeroen T. Buijs, Kasia M. Matula, Henry Cheung, Marianna Kruithof-De Julio, Maaike H. Van Der Mark, Thomas J. Snoeks, Ron Cohen, Willem E. Corver, Khalid S. Mohammad, Jos Jonkers, Theresa A. Guise, Gabri Van Der Pluijm

Research output: Contribution to journalArticle

2 Scopus citations

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 (60mg/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.

Original languageEnglish (US)
Pages (from-to)745-759
Number of pages15
JournalJournal of Pathology
Volume235
Issue number5
DOIs
StatePublished - Apr 1 2015

Keywords

  • breast cancer
  • invasive lobular carcinoma
  • metastasis
  • minimal residual disease
  • mouse model
  • receptor I kinase inhibitor
  • SD-208
  • TGFβ

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Buijs, J. T., Matula, K. M., Cheung, H., Kruithof-De Julio, M., Van Der Mark, M. H., Snoeks, T. J., Cohen, R., Corver, W. E., Mohammad, K. S., Jonkers, J., Guise, T. A., & Van Der Pluijm, G. (2015). Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; The effect of pharmacological targeting TGFβ receptor i kinase. Journal of Pathology, 235(5), 745-759. https://doi.org/10.1002/path.4488