Abstract 5109: MDM2 regulates intracellular pathways in TNBC and osteosarcoma that affect osteoclastogenesis

Abstract

Abstract Advanced cancer cells infiltrate and colonize new organ microenvironments through transformation of the dynamic metastatic niche. In bone, tumor cells secrete soluble factors that distort and manipulate normal bone remodeling leading to osteolytic lesions and inflammation. Clinically, primary high-grade bone sarcomas and secondary metastatic cancers exhibit elevated levels of murine double minute 2 (Mdm2), the principal cellular antagonist and E3 ubiquitin ligase of tumor suppressor p53. We demonstrate a novel function of mdm2, independent of p53, to drive osteolytic disease influenced by the signaling cascade of RANKL, ICAM1, and RANTES. To elucidate the direct influence of Mdm2 in cancer cells on osteoclast differentiation, several cell lines were created to overexpress or silence Mdm2. We found that osteoblast-like osteosarcoma (MG63, Saos2) and metastatic breast cancer cell lines (MDA468, MDA231, TMD-231, T47D, and BT474) lead to significant increased osteoclast differentiation, proliferation, and bone resorption. Co-cultures of Mdm2 over-expressing cancers and normal monocytes resulted in increased numbers of osteoclasts. In cancer cell lines where Mdm2 is silenced, we observed lower number of osteoclasts. The presence of Mdm2 in cancer cells also increased osteoclast resorption in an in vitro organ model. To determine the effects of ICAM1, we used an ICAM antibody to block ICAM1 in the media and showed a decrease in osteoclastogenesis. Understanding the role of Mdm2 in osteoclastogenesis may be amendable to translational benefit in disease models of advanced bone resorption and bone metastases. Citation Format: David J. Olivos, Lindsey D. Mayo. MDM2 regulates intracellular pathways in TNBC and osteosarcoma that affect osteoclastogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5109.