Abstract 1753: Comparison between early versus delayed treatment of breast cancer induced osteolytic bone metastasis by TGFβ inhibitors in a murine model

Abstract

Abstract In breast cancer patients the preferential metastasis to bone often causes considerable morbidity and mortality. Timely intervention is needed for the prevention and treatment of breast cancer-induced bone metastasis and osteolysis. Increased TGFβ signaling has been implicated to promote cancer cell invasion to bone and cause osteolysis. In this study we have evaluated the efficacy of the early and delayed start of treatment by TGFβ antagonists, TGFβ R1 kinase inhibitor (TβRI) and soluble TGFβ type III receptor (sRIII), in a murine bone metastasis model utilizing human breast cancer cells. The female athymic nude mice injected intracardiacally with human breast cancer MDA-MB-231 cells were divided into five groups (n=10). In the two early treatment groups, the i.p. treatment started on the same day of tumor cell inoculation and in the two delayed treatment groups, treatment started on the 8th day after tumor cell inoculation with TβRI (20 µg/mice) and sRIII (100 µg/mice) respectively and continued every alternate day. Control group of animals were injected with phosphate buffered saline. The experiment was terminated after 25 days. The incidence of osteolytic metastasis determined by Faxitron X-Ray of the legs and tumor burden by the histology of tibia was remarkably reduced in the early treatment group in comparison to the control group. On the other hand, the delayed start of the treatment showed little effect on the reduction of tumor burden and bone loss indicating better efficacy of early treatment by TGFβ inhibitors in preventing homing of the tumor cells into the bone. As a potential mechanism, we have investigated the role of TGFβ inhibitors in vitro on the bone marrow mesenchymal stem cell (BM-MSC) induced cancer cell invasion which has been implicated to facilitate early entry of breast cancer cell into bone marrow. We have observed that the medium conditioned by BM-MSCs stimulated the invasion of MDA-MB-231 cells, which was significantly inhibited by TGFβ antagonists. Our results point to the possible therapeutic utility of TGFβ inhibitors to prevent primarily the initiation of breast cancer-induced bone metastasis by the inhibition of homing of the tumor cells into the bone. The mechanism may involve the modulation of the bone marrow mesenchymal stem cell microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2011-1753