title: Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases.
abstract: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in human patients.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Aprelikova
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Tomlinson
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Hoenerhoff
authors.affiliation: Laboratory of Molecular Immunoregulation, NCI, NIH, Frederick, Maryland, United States of America.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hixon
authors.affiliation: Laboratory of Molecular Immunoregulation, NCI, NIH, Frederick, Maryland, United States of America.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Durum
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Ting-Hu
authors.initials: TH
authors.lastname: Qiu
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Siping
authors.initials: S
authors.lastname: He
authors.affiliation: Comparative Molecular Cytogenetics Core, Frederick National Laboratory for Cancer Research, NCI, Frederick, Maryland, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkett
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Zi-Yao
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001932:Brain Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007121:Immunocompetence; D008113:Liver Neoplasms / Q000556:secondary*; D008175:Lung Neoplasms / Q000556:secondary*; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008822:Mice, Transgenic; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000473:pathology; D013154:Spleen / Q000473:pathology; D019076:Transgenes; D047368:Tumor Burden; D014611:Vaccination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000952:Antigens, Polyomavirus Transforming