Abstract 2065: Loss of Nrf2 increases susceptibility to radiation induced bone loss

Abstract

Abstract A fundamental clinical complication in the treatment of patients with metastatic breast cancer is severe bone loss. Patients with breast cancer routinely received both chemotherapy and radiotherapy, both are known to increase oxidative stress and bone loss. Underlying mechanism of cancer therapy induced bone loss is poorly understood. We have previouslyreported that treatment with radiation (RT) increases TGFβ1 levels in mice. TGFβ1 increases oxidative stress by induction of reactive oxygen species (ROS). TGFβ1 increases oxidative stress by induction of reactive oxygen species (ROS). TGFβ1/Smad3 signaling suppresses Nrf2 (Nuclear factor erythroid-derived 2), a master transcription factor that positively regulates induction of antioxidant gene expression resulting in elevated ROS levels. Our objective is to test the hypothesis whether loss of Nrf2 gene increases the radiation induced bone loss. We have used age matched wild type control and Nrf2-/- mice. Mice were irradiated (single dose, 20 Gy) on the hind legs and microCT analysis was done to measure the overall bone loss. A similar increase in bone loss was noted in mice following histological analysis of the long bones. Additionally, reduction in osteoblast colony forming units and osteoblast differentiation were also noted. We have seen a higher number of osteoclasts in Nrf2-/- mice compared to wild type control and following radiation, the trend remains same. We conclude that, loss of Nrf2 leads to incraesed susceptibility to the radiation induced bone damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2065. doi:1538-7445.AM2012-2065