title: An improved syngeneic orthotopic murine model of human breast cancer progression.
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 .
authors.affiliation: Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, West Hospital 7-402, 1200 East Broad Street, PO Box 980011, Richmond, VA, 23298-0011, USA.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Rashid
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.forename: Suburamaniam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Catherine
authors.initials: C
authors.lastname: Dumur
authors.forename: Julia
authors.initials: J
authors.lastname: Schaum
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.forename: Krista P
authors.initials: KP
authors.lastname: Terracina
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D017690:Cell Transplantation / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008163:Luminescent Measurements; D008321:Mammary Glands, Animal / Q000601:surgery; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014183:Transplantation, Heterologous / Q000379:methods; D047368:Tumor Burden