A murine preclinical syngeneic transplantation model for breast cancer precision medicine

Lorenzo Federico, Zechen Chong, Dong Zhang, Daniel J. McGrail, Wei Zhao, Kang Jin Jeong, Christopher P. Vellano, Zhenlin Ju, Mihai Gagea, Shuying Liu, Shreya Mitra, Jennifer B. Dennison, Philip L. Lorenzi, Robert Cardnell, Lixia Diao, Jing Wang, Yiling Lu, Lauren A. Byers, Charles M. Perou, Shiaw Yih LinGordon Mills

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.

Original languageEnglish (US)
Article numbere1600957
JournalScience advances
Volume3
Issue number4
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Federico, L., Chong, Z., Zhang, D., McGrail, D. J., Zhao, W., Jeong, K. J., Vellano, C. P., Ju, Z., Gagea, M., Liu, S., Mitra, S., Dennison, J. B., Lorenzi, P. L., Cardnell, R., Diao, L., Wang, J., Lu, Y., Byers, L. A., Perou, C. M., ... Mills, G. (2017). A murine preclinical syngeneic transplantation model for breast cancer precision medicine. Science advances, 3(4), [e1600957]. https://doi.org/10.1126/sciadv.1600957