Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression

Lifsted, Traci; Voyer, Thomas Le; Williams, Max; Muller, William J.; Klein‐Szanto, Andres J.; Buetow, Kenneth H.; Hunter, Kent W.

doi:10.1002/(sici)1097-0215(19980812)77:4<640::aid-ijc26>3.0.co;2-8

Cited by 219 publications

(179 citation statements)

References 14 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…RI panels are a specialized genetic mapping resource that has unique properties that make them particularly valuable for the study of complex traits [20,21]. The AKXD RI mice are a particularly useful tool for the study of germline-encoded metastatic propensity since they are derived from AKR/ J, a highly metastatic strain, and DBA/2J, a weakly metastatic strain [7]. Detailed methodology for the generation of ECM eQTLs has been described previously [10].…”

Section: Results Eqtl Mapping In Akxd Recombinant Inbred Strains Revementioning

confidence: 99%

“…Work in our laboratory using the highly metastatic polyoma middle-T (PyMT) transgenic mouse model has demonstrated the significant influence of germline variation on tumor progression [7,8]. Tumors induced by the same oncogenic event, activation of the PyMT transgene, on different mouse genetic backgrounds were shown to have significantly different predilections for pulmonary metastasis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Crawford

Walker

Lukes

et al. 2008

Clin Exp Metastasis

Self Cite

View full text Add to dashboard Cite

Microarray expression signature analyses have suggested that extracellular matrix (ECM) gene dysregulation is predictive of metastasis in both mouse mammary tumorigenesis and human breast cancer. We have previously demonstrated that such ECM dysregulation is influenced by hereditary germline-encoded variation. To identify novel metastasis efficiency modifiers, we performed expression QTL (eQTL) mapping in recombinant inbred mice by characterizing genetic loci modulating metastasis-predictive ECM gene expression. Three reproducible eQTLs were observed on chromosomes 7, 17 and 18. Candidate genes were identified by correlation analyses and known associations with metastasis. Seven candidates were identified (Ndn, Pi16, Luc7l, Rrp1b, Brd4, Centd3 and Csf1r). Stable transfection of the highly metastatic Mvt-1 mouse mammary tumor cell line with expression vectors encoding each candidate modulated metastasis-predictive ECM gene expression. Implantation of these cells into mice demonstrated that candidate gene ectopic expression impacts tumor progression. Gene expression analyses facilitated the construction of a transcriptional network that we have termed the 'Diasporin Pathway'. This pathway contains the seven candidates, as well as metastasis-predictive ECM genes and metastasis suppressors. Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1. Furthermore, we demonstrate that the microarray gene expression signatures induced by activation of ECM eQTL genes in the Mvt-1 cell line can be used to accurately predict survival in a human breast cancer cohort. These data imply that the Diasporin Pathway may be an important nexus in tumor progression in both mice and humans.

show abstract

Section: Results Eqtl Mapping In Akxd Recombinant Inbred Strains Revementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Crawford

Walker

Lukes

et al. 2008

Clin Exp Metastasis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, convincing evidence of interactions between individual genes or categories of genes (e.g., enzymes) in neoplastic and nonneoplastic cells within tumors has appeared in some reports. 16,[36][37][38][39][40] Moreover, Creighton et al 41 conducted global gene expression analysis and showed a network of tumor-stromal molecular interactions in a primary tumor xenograft model of lung cancer. Our current report now provides specific evidence that, during metastasis, labeled cancer cells and neighboring host cell lineages of 3 different organs (breast, lung and lymph node), reproducibly and reciprocally alter the expression of multiple groups of genes coordinately, upon encountering each other and/or the intercellular materials that they produce.…”

Section: Discussionmentioning

confidence: 99%

Tumor–stromal interactions reciprocally modulate gene expression patterns during carcinogenesis and metastasis

Montel

Mose

Tarin

2006

Intl Journal of Cancer

View full text Add to dashboard Cite

This study used a unique xenogeneic breast cancer model to study the effects of tumor cells and neighboring host cells upon each other in tumor growth and metastasis. It exploited species differences between the interacting components to determine how the host influenced the tumor and vice versa. It was found that the gene expression profiles of highly and poorly metastatic clones from the same human breast carcinoma changed differentially when the cells were transferred from growth in vitro to the mammary gland. We describe novel sets of genes, validated by human-specific probes, which were induced in the 2 isogenic, but phenotypically different, tumor lineages by the mammary environment. Conversely, the tumor cells also induced changes in gene expression in the neighboring host stromal (i.e., mesenchymal) cell lineages, validated by mouse-specific probes. Reciprocal inductive interactions were also demonstrated in the tumor deposits formed preferentially in the lungs and lymph nodes by the highly metastatic tumor cells. Subtraction of the induced gene changes in the primary site from those in the metastases revealed that the number and magnitude of specific gene inductions in colonized organs were moderate. This finding indicates that the gene expression program causing metastasis has only limited flexibility and fits well with clinical observations that tumor cells form metastases preferentially in select organs, although tumor cells are scattered ubiquitously. This dependency on suitable host niches suggests new molecular therapeutic avenues that target genes in the host-support system that is manipulated by the malignant cells. To survive and prevail, the intruding cells must co-opt local conditions to provide their needs. This prompts questions about what interactions and mechanisms are activated to promote this disorderly behavior and how these are normally suppressed.The discoveries of Spemann and colleagues, 1 that cells of different embryonic lineages actively induce each other to cooperate in the formation of tissues, organs and body regions have far reaching applications in solving such fundamental but clinically relevant questions. Their findings provided a rational framework for explaining how specialized cell lineages interact to produce and maintain the anatomic plan of the whole animal and the microscopic architecture of its individual organs throughout life and healing processes. Conversely, their observations also have important implications for understanding mechanisms underlying the progressive histological disorganization which characterizes cancer pathogenesis and progression to metastatic malignancy. Important steps in recognizing the importance of cell and tissue interactions in neoplasia include the work of Orr that showed that morphological 2 and functional 3 changes occur in the dermis of carcinogen-treated skin long before a carcinoma develops from the overlying epidermis. Later, Grobstein 4 and Sengel et al. 5 showed that the formation of the microscopic anatomy and histology of org...

show abstract

“…The F 1 progeny were aged to permit tumour induction and potential metastatic dissemination. Subsequently, the lungs were examined to determine whether introduction of allelic variation had an affect on the density of pulmonary metastases, and a wide variation in metastatic efficiency was observed (Lifsted et al, 1998). Since all of the tumours were induced by the same genetic event, expression of PyVT, the most likely explanation for this variation is that subtle genetic differences between the strains are affecting the metastasis process.…”

Section: Genetic Modulation Of Metastasismentioning

confidence: 99%

Host genetics and tumour metastasis

Hunter

2004

Br J Cancer

View full text Add to dashboard Cite

Metastasis, the spread and growth of tumours at secondary sites, is an extremely important clinical event, since a majority of cancer mortality is associated with the metastatic tumours, rather than the primary tumour. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumour cells can be shed into the vasculature daily; yet, few secondary tumours are formed. The classical hypothesis explaining the inefficiency was a series of secondary events occurring in the tumour, resulting in a small subpopulation of cells capable of completing all of the steps required to successfully colonise a distant site. However, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumour tissue are not consistent with only a small subpopulation of cells in the primary tumour acquiring metastatic ability, suggesting that metastatic ability might be pre-programmed in tumours by the initiating oncogenic mutations. Data supporting both of these seemingly incompatible theories exist. Therefore, to reconcile the observed results, additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background on which a tumour arises on can have significant affects on the ability of the tumour to metastasise and on gene expression profiles. Thus, the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which, subsequently, metastasispromoting mutational and epigenetic events occur. If the genetic background is an important determinant of metastatic efficiency, it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies. Metastasis is an extraordinarily complex process. To successfully colonise a secondary site, a cancer cell must complete a sequential series of steps before it becomes a clinically detectable lesion. These steps include separation from the primary tumour, invasion through surrounding tissues and basement membranes, entry and survival in the circulation, lymphatics or peritoneal space, arresting in a distant target organ, usually, but not always (Al-Mehdi et al, 2000) followed by extravasation into the surrounding tissue, survival in the foreign microenvironment, proliferation, and induction of angiogenesis, all the while evading apoptotic death or immunological response (reviewed in Liotta and Stetler-Stevenson, 1993).This process is of great importance to the clinical management of cancer, since the majority of cancer mortality is associated with metastatic disease rather than the primary tumour (Liotta and Stetler-Stevenson, 1993). In most cases, cancer patients with localised tumours have significantly better prognoses than those wi...

show abstract

Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression

Cited by 219 publications

References 14 publications

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Tumor–stromal interactions reciprocally modulate gene expression patterns during carcinogenesis and metastasis

Host genetics and tumour metastasis

Contact Info

Product

Resources

About