Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

Hyunkeun Song, Tae O. Kim, Sun Y. Ma, Jin Hee Park, Jae Hyug Choi, Jin Ho Kim, Mi S. Kang, Sang K. Bae, Ki H. Kim, Tae H. Kim, Su Kil Seo, Il W. Choi, Geun A. Song, Eric D. Mortenson, Yang Xin Fu, Sae Gwang Park

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody.Methods: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody.Results: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy.Conclusion: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.

Original languageEnglish (US)
Article number647
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - Sep 1 2014

Keywords

  • Animal model
  • Anti-HER2/neu antibody
  • Antibody resistance
  • Breast cancer
  • Epithelial mesenchymal transition
  • Intratumoral heterogeneity
  • Spontaneous metastasis

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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  • Cite this

    Song, H., Kim, T. O., Ma, S. Y., Park, J. H., Choi, J. H., Kim, J. H., Kang, M. S., Bae, S. K., Kim, K. H., Kim, T. H., Seo, S. K., Choi, I. W., Song, G. A., Mortenson, E. D., Fu, Y. X., & Park, S. G. (2014). Intratumoral heterogeneity impacts the response to anti-neu antibody therapy. BMC Cancer, 14(1), [647]. https://doi.org/10.1186/1471-2407-14-647