Abstract
Tumor cells in bone can induce the activation of osteoclasts, which mediate bone resorption and release of growth factors and calcium from the bone matrix, resulting in a cycle of tumor growth and bone breakdown. Targeting the bone microenvironment by the inhibition of RANKL, an essential mediator of osteoclast function, not only prevents tumor-induced osteolysis but also decreases skeletal tumor burden in preclinical models. The inhibition of skeletal tumor progression after the inhibition of osteoclasts is via interruption of the “vicious cycle” of tumor/bone interactions. The majority of breast cancer patients at risk for bone metastases harbor estrogen receptor-positive (ER+) tumors. We developed a mouse model for ER+ breast cancer bone metastasis and evaluated the effect of RANKL inhibition on tumor-induced osteolysis and skeletal tumor growth both alone and in combination with tamoxifen. Luciferase-labeled MCF-7 cells (MCF-7Luc) formed metastatic foci in the hind limbs following intracardiac injection and caused mixed osteolytic/osteoblastic lesions. RANKL inhibition by OPG-Fc treatment blocked osteoclast activity and prevented tumor-induced osteolysis, as well as caused a marked decrease in skeletal tumor burden. Tamoxifen as a single agent reduced MCF-7Luc tumor growth in the hind limbs. In a combination experiment, OPG-Fc plus tamoxifen resulted in significantly greater tumor growth inhibition than either single agent alone. Histologic analysis revealed a decrease in the proliferation of tumor cells by both single agents, which was enhanced in the combination treatment. Upon treatment with OPG-Fc alone or in combination with tamoxifen, there was a complete absence of osteolytic lesions, demonstrating the ability of RANKL inhibition to prevent skeletal related morbidity in an ER+ model. The combination approach of targeting osteoclasts and the bone microenvironment by RANKL inhibition and the tumor directly via hormonal therapy may provide additional benefit to reducing skeletal tumor progression in ER+ breast cancer patients.
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Acknowledgments
We thank Angela Coxon for critical review of the manuscript and Geoff Smith for editorial assistance.
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All authors are employees of Amgen, Inc. and have received stock/stock options from Amgen, Inc.
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All experiments conducted herein comply with the laws of the United States of America.
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10549_2012_2222_MOESM1_ESM.pdf
Supplemental Fig. 1. OPG-Fc treatment did not affect the subcutaneous growth of MCF-7Luc cells. Tumor cells were implanted into the flank and treatment with either PBS or OPG-Fc (3 mg/kg, 3×/week) began on day 36 post tumor implantation. Data represent mean tumor volume ± SEM for each group (N = 10/group). (PDF 4 kb)
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Canon, J., Bryant, R., Roudier, M. et al. RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. Breast Cancer Res Treat 135, 771–780 (2012). https://doi.org/10.1007/s10549-012-2222-2
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DOI: https://doi.org/10.1007/s10549-012-2222-2