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

Sadanandam, Anguraj; Futakuchi, Mitsuru; Lyssiotis, Costas A.; Gibb, William J.; Singh, Rakesh K.

doi:10.1186/1471-2407-11-304

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

Journal Article · Wed Jul 20 00:00:00 EDT 2011 · BMC Cancer

DOI:https://doi.org/10.1186/1471-2407-11-304· OSTI ID:1626524

Sadanandam, Anguraj ^[1]; Futakuchi, Mitsuru ^[2]; Lyssiotis, Costas A. ^[3]; Gibb, William J. ^[4]; Singh, Rakesh K. ^[5]

Univ. of Nebraska Medical Center, Omaha, NE (United States). Dept. of Pathology and Microbiology; Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne (Switzerland). Swiss Inst. for Experimental Cancer Research (ISREC)
Nagoya City Univ., Nagoya (Japan). Graduate School of Medical Sciences. Dept. of Molecular Toxicology
Harvard Medical School, Boston, MA (United States). Dept. of Systems Biology; Beth Israel Deaconess Medical Center, Boston, MA (United States). Division of Signal Transduciton
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Dept. of Life Sciences
Univ. of Nebraska Medical Center, Omaha, NE (United States). Dept. of Pathology and Microbiology

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-b 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231; CA71781; P30CA036727; KG090860

OSTI ID:: 1626524

Journal Information:: BMC Cancer, Vol. 11, Issue 1; ISSN 1471-2407

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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tumor-bone microenvironment
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