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An improved syngeneic orthotopic murine model of human breast cancer progression

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Abstract

Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development .

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Acknowledgments

The authors thank the Virginia Commonwealth University Health System Anatomic Pathology Research Services (APRS) Director Dr. Jorge A. Almenara and histotechnologists for technical assistance in the tissue processing, sectioning and staining. NIH grants (R01CA160688) and Susan G. Komen for the Cure Investigator Initiated Research Grant (IIR12222224) to KT, and NCI grant R01CA61774 to SS. MN is a Japan Society for the Promotion of Science Postdoctoral Fellow.

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All authors have no conflicts of interest in regards to the content of this manuscript.

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Correspondence to Kazuaki Takabe.

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Rashid, O.M., Nagahashi, M., Ramachandran, S. et al. An improved syngeneic orthotopic murine model of human breast cancer progression. Breast Cancer Res Treat 147, 501–512 (2014). https://doi.org/10.1007/s10549-014-3118-0

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