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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

Pathobiology of the 129:Stat1 −/− mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype

Authors: Hidetoshi Mori, Jane Q. Chen, Robert D. Cardiff, Zsófia Pénzváltó, Neil E. Hubbard, Louis Schuetter, Russell C. Hovey, Josephine F. Trott, Alexander D. Borowsky

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

Stat1 gene-targeted knockout mice (129S6/SvEvTac-Stat1 tm1Rds) develop estrogen receptor-positive (ER+), luminal-type mammary carcinomas at an advanced age. There is evidence for both host environment as well as tumor cell-intrinsic mechanisms to initiate tumorigenesis in this model. In this report, we summarize details of the systemic and mammary pathology at preneoplastic and tumor-bearing time points. In addition, we investigate tumor progression in the 129:Stat1 −/− host compared with wild-type 129/SvEv, and we describe the immune cell reaction to the tumors.

Methods

Mice housed and treated according to National Institutes of Health guidelines and Institutional Animal Care and Use Committee-approved methods were evaluated by histopathology, and their tissues were subjected to immunohistochemistry with computer-assisted quantitative image analysis. Tumor cell culture and conditioned media from cell culture were used to perform macrophage (RAW264.7) cell migration assays, including the 129:Stat1 −/−-derived SSM2 cells as well as control Met1 and NDL tumor cells and EpH4 normal cells.

Results

Tumorigenesis in 129:Stat1 −/− originates from a population of FoxA1+ large oval pale cells that initially appear and accumulate along the mammary ducts in segments or regions of the gland prior to giving rise to mammary intraepithelial neoplasias. Progression to invasive carcinoma is accompanied by a marked local stromal and immune cell response composed predominantly of T cells and macrophages. In conditioned media experiments, cells derived from 129:Stat1 −/− tumors secrete both chemoattractant and chemoinhibitory factors, with greater attraction in the extracellular vesicular fraction and inhibition in the soluble fraction. The result appears to be recruitment of the immune reaction to the periphery of the tumor, with exclusion of immune cell infiltration into the tumor.

Conclusions

129:Stat1 −/− is a unique model for studying the critical origins and risk reduction strategies in age-related ER+ breast cancer. In addition, it can be used in preclinical trials of hormonal and targeted therapies as well as immunotherapies.
Appendix
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Metadata
Title
Pathobiology of the 129:Stat1 −/− mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype
Authors
Hidetoshi Mori
Jane Q. Chen
Robert D. Cardiff
Zsófia Pénzváltó
Neil E. Hubbard
Louis Schuetter
Russell C. Hovey
Josephine F. Trott
Alexander D. Borowsky
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0892-8

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