Abstract 5070: Sulforaphane is a novel inhibitor of breast cancer-induced osteolytic bone resorption

Abstract

Abstract Bone is the preferred site for metastatic spread in women with advanced breast cancer, and skeletal complications is associated with high morbidity and mortality. Nearly 70% of luminal-type breast cancer patients with metastases to bone experience skeletal complications due to enhanced osteoclastogenesis (osteoclast activation) that increases bone resorption, pain, pathological fractures, spinal cord compression, and hypercalcemia. The present study was designed to determine the effect of a cruciferous vegetable component (Sulforaphane; SFN) on breast cancer-induced osteoclastogenesis. Osteoclast differentiation in mouse bone marrow monocytes (BMM) was inhibited significantly upon the addition of 10% conditioned-media (CM) from SFN-treated breast cancer cells belonging to different subtypes, including MDA-MB-231, MCF-7, and SK-BR-3, in comparison with corresponding control. PCR-based gene expression profiling identified a common set of genes downregulated by SFN treatment compared to vehicle-treated control in MDA-MB-231, MCF-7, and SK-BR-3 cells, including osteoclastogenesis promoting transcription factors (RUNX2, NF-κB, and SOX-9) and certain soluble molecules (MMP9, TNFα, and Cathepsin K). Many of these gene expression changes were confirmed in MDA-MB-231, MCF-7, and SK-BR-3 cells by RT-PCR or western blotting. To determine the in vivo efficacy, SFN was administrated orally (1 mg per mouse; three times/week) to athymic mice intracardially injected with MDA-MB-231-Luc cells. SFN administration significantly inhibited the multiplicity of bone metastases and increased the bone volume relative to total volume. SFN-mediated prevention of osteoclastogenesis was associated with a significant decrease in TRAP-positive osteoclasts in bones and the levels of Cathepsin K, IL-8, and RANKL in serum. Altogether, this study demonstrates, for the first time to the best of our knowledge, that SFN is a potent inhibitor of breast cancer-induced osteoclastogenesis and bone resorption in vitro and in vivo. This study was partly funded by a pilot project grant from the UPMC Hillman Cancer (NCI grant P30 CA047904; Robert L. Ferris- Principal Investigator) and RO1 CA142604 and CA129347 awarded by the National Cancer Institute (Shivendra Singh- Principal Investigator). Citation Format: Subrata K. Pore, Joseph D. Latoche, Carolyn J. Anderson, Juraj Adamik, Deborah L. Galson, Kurt R. Weiss, Boeun Lee, Rebecca J. Watters, Prashant N. Kumta, Shivendra V. Singh. Sulforaphane is a novel inhibitor of breast cancer-induced osteolytic bone resorption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5070.