Abstract 4114: Dual cytoprotective and cytotoxic functions of autophagy in the response of breast tumor cells to radiation and in radiosensitization by vitamin D3

Abstract

Abstract Introduction: While chemotherapy and radiation treatment may be initially effective at suppressing breast cancer growth, disease recurrence and tumor metastasis are major clinical problems. A number of strategies have been developed in an attempt to enhance the response to radiation and prevent tumor cell recovery by interfering with cytoprotective signaling. Autophagy reflects a cellular response to stress that allows the degradation of subcellular organelles to generate energy and metabolic precursors; autophagy may be cytoprotective or cytotoxic, depending on the cells and the nature of the stressful challenge. Our current studies were designed to evaluate the involvement of autophagy in radiosensitization by EB1089 as well as extending the work to the hormonally active and natural form of 1,25D3. In addition, studies were performed in breast tumor cells that are intrinsically resistant to radiation and chemotherapy through over expression of Her-2/neu (MCF7/Her-2/neu cells), as well as Hs578t cells and BT474 cells. Results: In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 enhanced radiosensitivity and promoted autophagy in MCF7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D3 with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D3). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy. Supported, in part, by American Institute for Cancer Research Grant # 06A058-REV and by a DOD predoctoral training grant (W81XWH-09-1-0020). 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 4114. doi:1538-7445.AM2012-4114