Of Mice and Women: A Short History of Mouse Mammary Cancer Research with an Emphasis on the Paradigms Inspired by the Transplantation Method

Medina, Daniel

doi:10.1101/cshperspect.a004523

Cited by 36 publications

(23 citation statements)

References 72 publications

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“…The role of natural genetic variation in mammary ductal development and susceptibility to cancer has been documented for many years (Medina 2010). In this regard, early studies on select inbred mouse strains demonstrated a link between the extent of ductal development and later development of mammary tumors (Apolant 1906; Gardner and Strong 1935; Gibson 1930; Haaland 1911).…”

Section: Introductionmentioning

confidence: 99%

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

Hadsell

Olea

et al. 2015

Mamm Genome

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Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetic diversity in mammary gland development is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structural variation in mammary ductal development, and determined if these QTL correlated with genomic intervals conferring breast cancer susceptibility in humans. For about half of the traits, the observed variation among the complete set of strains in this study was greater (P<0.05) than that observed with previously studied strains or with strains that are in current common use for mammary gland biology. Correlations were also detected with previously reported variation in mammary tumor latency and metastasis. In silico genome-wide association (GWAS) identified 20 mammary development QTL (Mdq). Of these, 5 were syntenic with previously reported human BrCa loci. The most highly significant (P=1×10 −11 ) association of the study was on MMU6 and contained the genes Plxna4, Plxna4os1, and Chchd3. On MMU5, a QTL was detected (p=8×10 −7 ) that was syntenic to a human BrCa locus on h12q24.5 containing the genes Tbx3 and Tbx5. Intersection of highassociation SNP (r 2 >0.8) with genomic and epigenomic features, and intersection of candidate genes with gene expression and survival data from human BrCa highlighted several for further study. These results support the conclusion that genetic variation in mammary ductal development is greater than previously appreciated. They also suggest that mammary tumor latency and metastatic index may be influenced by variations in the same factors that control normal mammary ductal development and that further studies of genetically diverse mice can improve our understanding of the connection between breast development and breast cancer in humans by identifying novel susceptibility genes. HHS Public Access

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Section: Introductionmentioning

confidence: 99%

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

Hadsell

Olea

et al. 2015

Mamm Genome

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“…To address this concern, we transplanted Pttg1 +/+ and Pttg1 −/− mammary gland tissues into the cleared fat pads of WT recipient mice. The WT and the mutant mammary tissues were placed in the same mouse (WT on one side and the mutant on another) (19,20). The transplants were allowed to develop uninterruptedly and were harvested for analysis at 5 and 8 wk after the procedure.…”

Section: Significancementioning

confidence: 99%

Pttg1/securin is required for the branching morphogenesis of the mammary gland and suppresses mammary tumorigenesis

Hatcher

Dong

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Pituitary tumor transforming gene 1 (Pttg1) encodes the mammalian securin, which is an inhibitor of separase (a protease required for the separation of sister chromatids in mitosis and meiosis). PTTG1 is overexpressed in a number of human cancers and has been suggested to be an oncogene. However, we found that, in Pttg1-mutant females, the mammary epithelial cells showed increased proliferation and precocious branching morphogenesis. In accord with these phenotypic changes, progesterone receptor, cyclin D1, and Mmp2 were up-regulated whereas p21 (Cdkn1a) was down-regulated. These molecular changes provide explanation for the observed developmental defects, and suggest that Pttg1 is a tumor suppressor. Indeed, mice lacking Pttg1 developed spontaneous mammary tumors. Furthermore, in human breast tumors, PTTG1 protein levels were down-regulated and the reduction was significantly correlated with the tumor grade.

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“…After serial transplantation, normal mammary tissues senesce after several generations (Daniel and Young 1971). The history and experimental details involving the development of these techniques is provided in the articles by Medina (2010) and Cardiff and Kenney (2011).…”

Section: Nongermline Genetically Engineered Mouse Modelsmentioning

confidence: 99%

Choosing a Mouse Model: Experimental Biology in Context--The Utility and Limitations of Mouse Models of Breast Cancer

Borowsky¹

2011

Cold Spring Harbor Perspectives in Biology

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Genetically engineered mice are critical experimental models for the study of breast cancer biology. Transgenic mice, employing strong mammary epithelial promoters to drive oncogenes, develop carcinomas with phenotypes corresponding to the molecular pathway activated. Gene-targeted (knockout) mice, in which tumor suppressors are deleted, develop mammary neoplasms with phenotypes primarily including patterns seen in spontaneous mouse mammary tumors, albeit at higher rates. Improved genetic engineering, using inducible gene expression, somatic gene transduction, conditional alleles, and crossbreeding for combined/compound genetic engineering yields precise molecular models with exquisite experimental control and phenotypes with comparative pathologic validity. Mammary gland transplantation technology adds a practical and validated method for assessing biologic behavior of selected mammary tissues. Overall, the many mouse models available are a rich resource for experimental biology with phenocopies of breast cancer subtypes, and a variety of practical advantages. The challenge is matching the model to the experimental question.T here is no perfect model system for studying breast cancer. Breast cancer in women constitutes an array of different diseases, and it is not realistic to consider breast cancer as a single disease. Experimental models are needed to reflect each part of the array. Cell culture lines are the most practical, and a panel of 51 standard cell lines is currently available reflecting most of the intrinsic subtypes of breast cancer (Neve et al. 2006). These cell lines are adapted to growth on two-dimensional (2D) plastic dishes and represent an oversimplified biology out of context. Growth in 3D culture is more contextual, but still simplified (Kenny et al. 2007). Even xenografting of human cell lines in mice is artificial, short-circuiting the precancer stage, the development of a permissive environment, and eliminating the immune system. Mouse models, particularly the genetically defined models offer a step in the direction of biologic reality. Choosing among the mouse models of breast cancer is not a trivial exercise. Literally thousands of specifically engineered mice have been created to study the pathology, molecular biology, natural history, and response to therapy in breast cancer (Borowsky 2007).

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Of Mice and Women: A Short History of Mouse Mammary Cancer Research with an Emphasis on the Paradigms Inspired by the Transplantation Method

Cited by 36 publications

References 72 publications

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

Pttg1/securin is required for the branching morphogenesis of the mammary gland and suppresses mammary tumorigenesis

Choosing a Mouse Model: Experimental Biology in Context--The Utility and Limitations of Mouse Models of Breast Cancer

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