Abstract
BackgroundStat1 gene-targeted knockout mice (129S6/SvEvTac-Stat1tm1Rds) 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.MethodsMice 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.ResultsTumorigenesis 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.Conclusions129: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.
Highlights
Stat1 gene-targeted knockout mice (129S6/SvEvTac-Stat1tm1Rds) develop estrogen receptor-positive (ER+), luminal-type mammary carcinomas at an advanced age
We report the findings of additional morphological abnormalities in the Stat1−/− mouse that reflect systemic endocrine and environment effects, as well as the identification of a Forkhead box A1 (FoxA1)+ large oval pale (LOP) cell that appears along some Stat1-null ducts as their hosts approach tumor-bearing age
The tumor incidence in our cohort remained consistent after 1 year of age (35%), subsequent pathological analysis revealed that surviving nulliparous females had mammary intraepithelial neoplasia (MIN) lesions, suggesting that the penetrance of mammary tumors could approach 100% were animals to age even further
Summary
Stat gene-targeted knockout mice (129S6/SvEvTac-Stat1tm1Rds) develop estrogen receptor-positive (ER+), luminal-type mammary carcinomas at an advanced age. Stat1-null females exhibit a prolonged tumor latency that models the majority of human breast cancers that are age-related [2, 7, 8]. Given these relevant characteristics, we sought to investigate the origins, evolution, and progression of tumors in the context of the whole animal, with detailed observations afforded by anatomic, histologic, endocrine function, immune cell reaction, and molecular evaluations of organs from aged 129:Stat1−/− mice [9,10,11,12]. Reciprocal mammary gland transplantation in immune intact syngeneic 129/SvEv and in 129:Stat1−/− mice, as well as tissue coculture experiments, has facilitated isolation and investigation of the host environment [7]
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