Abstract 1336: Characterization of a novel transplantable model of obesity-driven basal-like breast cancer
Authors: Carson Meredith S. , Glenny Elaine M. , Kiesel Violet A. , Taylor Ashlee , Roth Daniel , Albright Jody , VerHague Melissa , French John E. , Coleman Michael F. , Hursting Stephen D. 
Published: June 2022

Introduction: Breast cancer (BC) is a leading cause of cancer-related death in women, with the poorest prognosis found in the basal-like subtype. Although obesity is an established risk factor for basal-like BC, existing mouse models to study the interaction of basal-like BC and diet-induced obesity (DIO) are limited. The C3(1)/SV40 large T-antigen (TAg) transgenic mouse is an established, human-relevant basal-like mammary cancer model developed on an obesity-resistant FVB genetic background. The goal of this study was to create and characterize a transplantable C3TAg model on an obesity-sensitive C57BL/6J (B6) genetic background.

Methods: Male C3TAg transgenic FVB mice were backcrossed with female wild-type B6 mice for 10 generations. Spontaneous mammary tumors from these female B6:C3TAg mice were dissociated and subcloned, generating 4 distinct cell lines differing in their expression of metabolic genes. A pilot orthotopic transplant study using the 4 candidate cell lines (at 3 cell concentrations of each line) in 96 B6 mice identified cell line 2.51 as an attractive model for further evaluation based on in vivo growth characteristics and initial genomic analyses. To assess the impact of DIO in this model, 61 female B6 mice were randomized to receive either control (n=30) or DIO (n=31) diet regimens for 24 weeks, then were orthotopically injected into the 4th mammary fat pad with cell line 2.51 (2.5x105 cells/mouse). The mice continued on their respective diets, were monitored for tumor development, and were euthanized 4 weeks post-injection. Tumors were collected, weighed and flash frozen for genomic, immunologic and biochemical analyses.

Results: All 4 cell lines tested in the pilot study generated basal-like mammary tumors when orthotopically transplanted. Tumor gene expression profiling (via Affymetrix microarray) revealed inflammation and stem-like gene expression profiles discordant between cell lines tested, with tumors induced by cell line 2.51 showing striking enrichment in immune signatures relative to the other cell lines. DIO, relative to control diet, significantly accelerated transplanted 2.51 cell tumor progression, as indicated by increased tumor mass in mice from DIO relative to control diet-fed animals. Genomic, biochemical, and immunological assessment of the tumor-enhancing effects of DIO in this model are ongoing.

Conclusions: Herein, we report the development and characterization of a novel transplantable C3TAg mammary tumor model in C57BL/6J mice, highly responsive to energy balance. This work represents a promising new tool for preclinical studies of the interactions between diet, obesity, immunity and basal-like breast cancer.

Funding: This work was supported by R35CA197627 to SDH.

Citation Format: Meredith S. Carson, Elaine M. Glenny, Violet A. Kiesel, Ashlee Taylor, Daniel Roth, Jody Albright, Melissa VerHague, John E. French, Michael F. Coleman, Stephen D. Hursting. Characterization of a novel transplantable model of obesity-driven basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1336.