Abstract
BackgroundBreast 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.MethodsIn 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.ResultsWe 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.ConclusionOur 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.
Highlights
Breast cancer is the second leading cause of cancer-related death in women in the United States
Irrespective of the cell lines used, histochemical analysis of these tumors demonstrated that they exhibited tumor-induced osteolysis and osteoclast activation similar to that observed in breast cancer bone metastasis [12,14]
Metastatic lesions from the osteolytic tumors were microdissected into two cohorts - tumor bone (TB) interface and tumor alone (TA) area - and gene expression profile analyses were performed [12,14]
Summary
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. Arguello, et al developed a model in which melanoma cells injected into the left ventricle of the heart form bone metastases [7] This model was later used to study various mechanisms behind breast cancer-specific osteoclast formation and bone metastasis [8,9,10]. Our group has developed a rat model to study bone metastatic microenvironment in which prostate tumors were directly transplanted onto the calvariae of syngeneic animals These tumors exhibited pathological osteoblastic and osteoclastic changes [11]. While this series of observations has furthered our understanding of the mechanisms underlying osteolysis, their relevance to human breast cancer remained unknown
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