Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in promoting breast cancer growth and progression. While the autocrine effects of FGFR activation in tumor cells have been extensively studied, little is known about the effects of tumor cell-derived FGFs on cells in the microenvironment. Because FGF signaling has been implicated in the regulation of bone formation and osteoclast differentiation, we hypothesized that tumor cell-derived FGFs are capable of modulating osteoclast function and contributing to growth of metastatic lesions in the bone. Initial studies examining FGFR expression during osteoclast differentiation revealed increased expression of FGFR1 in osteoclasts during differentiation. Therefore, studies were performed to determine whether tumor cell-derived FGFs are capable of promoting osteoclast differentiation and activity. Using both non-transformed and transformed cell lines, we demonstrate that breast cancer cells express a number of FGF ligands that are known to activate FGFR1. Furthermore our results demonstrate that inhibition of FGFR activity using the clinically relevant inhibitor BGJ398 leads to reduced osteoclast differentiation and activity in vitro. Treatment of mice injected with tumor cells into the femurs with BGJ398 leads to reduced osteoclast activity and bone destruction. Together, these studies demonstrate that tumor cell-derived FGFs enhance osteoclast function and contribute to the formation of metastatic lesions in breast cancer.
Highlights
While the 5-year survival rate for breast cancer patients has increased to 89% overall, the 5-year survival rate for patients diagnosed with metastatic breast cancer remains low at 24% [1]
FGF receptors (FGFRs) expression levels during osteoclast differentiation have not been previously examined, Chikazu et al demonstrated that mature osteoclasts express only FGFR1 [21]
To determine whether this increase was due to transcriptional regulation of Fgfr1, further studies were performed using qRT-PCR analysis of gene expression of the different FGFR isoforms
Summary
While the 5-year survival rate for breast cancer patients has increased to 89% overall, the 5-year survival rate for patients diagnosed with metastatic breast cancer remains low at 24% [1]. Breast cancer metastasizes to several sites including lung, liver, brain and bone, with bone being the preferred site [2]. Bone micrometastases are present in 30% of patients diagnosed with stage I, II and III (non-metastatic) breast cancer and the presence of bone micrometastasis is an independent predictor of poor outcome [3]. Over 70% of advanced breast cancer patients develop overt bone metastasis emphasizing the clinical importance of this phenomenon. There are limited therapeutic options for managing the clinical impact of bone metastases, other than palliative therapies. There is an urgent need for developing novel therapies that can be used to help limit the growth and deleterious sequelae of breast tumor lesions localized to bone
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