Abstract
Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.
Highlights
Breast cancer remains the second leading cause of cancerrelated death among women, in recent years there has been significant advancement in terms of treatment and prevention
Following 4-weeks of treatment, anti-TGFb treatment significantly reduced the tumor burden in the long bones (p value = 0.001; Figure 1b) and only microscopic small foci of tumor cells were observed in most mice treated with 1D11 (Figure 1a, white line indicates area occupied by tumor)
Following 2-weeks treatment, a similar but less dramatic effect was observed (p value = 0.016; Figure 1c). To test whether this treatment was effective in other bone metastases models, female Balb/C mice was inoculated with 4T1 murine mammary breast cancer cells and mice were treated one day after tumor cell inoculation and continued to be treated for 4 weeks
Summary
Breast cancer remains the second leading cause of cancerrelated death among women, in recent years there has been significant advancement in terms of treatment and prevention. Mohammad et al have recently shown that a small molecule inhibitor of TGFb was able to inhibit melanoma bone disease in a preclinical model [33] Whether these approaches improve breast cancer-induced bone loss has not yet been reported. Our group recently reported that the anti-TGFb antibody has the potential to increase bone volume in normal mice [35] These results prompted us to test the efficacy of anti-TGFb antibody in preventing cancer-induced bone disease. 1D11 was able to block TGFb induced expression of both Gli and PTHrP, which provides a mechanistic explanation of reduced tumor burden in our model To our knowledge, this is the first demonstration of dual efficacy of an anti-TGFb antibody to both inhibit tumor burden and rescue bone loss in a breast cancer to bone metastasis model [33]
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