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- Title
Development and Characterization of Syngeneic Orthotopic Transplant Models of Obesity-Responsive Triple-Negative Breast Cancer in C57BL/6J Mice.
- Authors
Carson, Meredith S.; Rädler, Patrick D.; Albright, Jody; VerHague, Melissa; Rezeli, Erika T.; Roth, Daniel; French, John E.; Perou, Charles M.; Hursting, Stephen D.; Coleman, Michael F.
- Abstract
Simple Summary: Transplanting cell lines into the mammary fat pad of lean and obese mice is a powerful tool to understand how breast cancer is promoted by obesity. However, for this approach to be effective, well-characterized and appropriate cell lines are needed. Here, we have developed four readily tumorigenic claudin-low triple-negative breast cancer cell lines from tumors arising from C3-TAg transgenic C57BL6 mice (B6TAg). We employ transcriptomic analysis of in vitro and in vivo samples to delineate distinct transcriptomic signatures in each cell line. We demonstrate that tumor progression of the three most distinct cell lines was accelerated by diet-induced obesity. Taken together, our data establish these B6TAg cell lines as potentially potent tools to delineate how obesity promotes triple-negative breast cancer progression. Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC), but preclinical studies to delineate the mechanisms underlying the obesity-TNBC link as well as strategies to break that link are constrained by the lack of tumor models syngeneic to obesity-prone mouse strains. C3(1)/SV40 T-antigen (C3-TAg) transgenic mice on an FVB genetic background develop tumors with molecular and pathologic features that closely resemble human TNBC, but FVB mice are resistant to diet-induced obesity (DIO). Herein, we sought to develop transplantable C3-TAg cell lines syngeneic to C57BL/6 mice, an inbred mouse strain that is sensitive to DIO. We backcrossed FVB-Tg(C3-1-TAg)cJeg/JegJ to C57BL/6 mice for ten generations, and spontaneous tumors from those mice were excised and used to generate four clonal cell lines (B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51). We characterized the growth of the four cell lines in both lean and DIO C57BL/6J female mice and performed transcriptomic profiling. Each cell line was readily tumorigenic and had transcriptional profiles that clustered as claudin-low, yet markedly differed from each other in their rate of tumor progression and transcriptomic signatures for key metabolic, immune, and oncogenic signaling pathways. DIO accelerated tumor growth of orthotopically transplanted B6TAg1.02, B6TAg2.03, and B6TAg2.51 cells. Thus, the B6TAg cell lines described herein offer promising and diverse new models to augment the study of DIO-associated TNBC.
- Subjects
BIOLOGICAL models; IN vitro studies; TRANSPLANTATION of organs, tissues, etc.; DATA analysis; T-test (Statistics); RESEARCH funding; BREAST tumors; INTERNAL thoracic artery; IMMUNE system; CELLULAR signal transduction; MANN Whitney U Test; DESCRIPTIVE statistics; CELL lines; MICE; METABOLITES; RNA; ANIMAL experimentation; GENE expression profiling; ONE-way analysis of variance; STATISTICS; ANALYSIS of variance; SURVIVAL analysis (Biometry); DATA analysis software; OBESITY; DISEASE progression; SEQUENCE analysis
- Publication
Cancers, 2024, Vol 16, Issue 16, p2803
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16162803