Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis.

Yuan Yang,Maxwell P Lee,Thomas R Geiger,Diana C Haines,Kent W Hunter,Philip Martin,Ying Hu,Peter H Watson,Huaitian Liu,Miriam R Anver,Howard H Yang,Jeffrey E Green,Lalage M Wakefield

doi:10.18632/oncotarget.15695

Abstract

Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts. Genomic characterization shows that more than half of the 30 most commonly mutated genes in human breast cancer are represented within the panel. Transcriptomically, most of the models fall into the luminal A or B intrinsic molecular subtypes, despite the predominance of an aggressive, poorly-differentiated or spindled histopathology in all models. Patterns of immune cell infiltration, proliferation rates, apoptosis and angiogenesis differed significantly among models. Inherent within-model variability of the metastatic phenotype mandates large cohort sizes for intervention studies but may also capture some relevant non-genetic sources of variability. The varied molecular and phenotypic characteristics of this expanded panel of models should aid in model selection for development of antimetastatic therapies in vivo, and serve as a useful platform for predictive biomarker identification.

Highlights

Metastasis is the most lethal aspect of the carcinogenic process, and the prognosis for patients with disseminated disease at diagnosis is dismal, with fiveyear survival rates of less than 25% in breast cancer [1]
These include the MDA-MB-231 human breast cancer cell line xenografted into immunodeficient mice, the 4T1 murine mammary cancer cell line allografted into syngeneic immunocompetent mouse hosts [6], and the genetically engineered MMTV-PyVT mouse model of metastatic breast cancer [7]
Half the models were derived from spontaneously arising mammary tumors, and half were derived from genetically engineered mouse models (GEMM)

Summary

Introduction

Metastasis is the most lethal aspect of the carcinogenic process, and the prognosis for patients with disseminated disease at diagnosis is dismal, with fiveyear survival rates of less than 25% in breast cancer [1]. The information that we have about the biology of the metastatic process and the response of metastases to therapy is generalized from a very small number of widely-used models In breast cancer, these include the MDA-MB-231 human breast cancer cell line xenografted into immunodeficient mice [4, 5]), the 4T1 murine mammary cancer cell line allografted into syngeneic immunocompetent mouse hosts [6], and the genetically engineered MMTV-PyVT mouse model of metastatic breast cancer [7]. While these models have indisputably generated many useful mechanistic insights, they do not begin to capture the heterogeneity of human breast cancer

Methods

Results

Conclusion