A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

BMC Cancer

Anguraj Sadanandam⁵  Mitsuru Futakuchi³  Costas A Lyssiotis²  William J Gibb¹  Rakesh K Singh⁴ 

[1] Department of Life Sciences, Lawrence Berkeley National Lab, Berkeley, CA 94702, USA

[2] Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA

[3] Department of Molecular Toxicology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan

[4] Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA

[5] Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

关键词: thiazide;    tumor-bone microenvironment;    bone metastasis;    Osteolysis;   

Others  :  1080831
DOI  :  10.1186/1471-2407-11-304

 received in 2010-08-02, accepted in 2011-07-20,  发布年份 2011

【 摘 要 】

Background

Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. In vivo models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.

Methods

In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.

Results

We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an in vitro osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.

Conclusion

Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.

【 授权许可】

   
2011 Sadanandam et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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