Abstract 4118: Reducing the effects of glucocorticoids on breast cancer outcome <i>in-vitro</i> and <i>in-vivo</i>
Authors: Kristina Andrijauskaite
Journal: Cancer Research (2020)

Abstract Background: Research indicates that natural and synthetic glucocorticoids (GCs) may play a role in cancer progression and patient survival. The main natural GC is cortisol which is released during psychological stress. Whereas, synthetic GCs, such as dexamethasone, are widely used in conjugation with cancer therapy due to their ability to induce apoptosis. Surprisingly, recent evidence suggests that GCs can induce therapy-resistance in solid tumors, although the precise mechanisms are not well defined. The goal of this study was to assess the role of natural and synthetic GCs on resistance to cytotoxic therapy in breast cancer and to examine the usage of a novel supercritical plant extract derived from the neem tree (SCNE) in reversing the antagonizing effects of GCs. Methods: We co-treated human breast cancer cells (MDA-MB-231) with physiological and therapeutic doses of cortisol and dexamethasone (0.1-10 µM) alone or in combination with chemotherapy drug Fluorouracil (5FU) and SCNE for 72 hours. We performed cell viability, proliferation, cell cycle, flow cytometry, and apoptosis assays. Thus, we used the glucocorticoid receptor (GR) antagonist (RU-486) to investigate the role of GC receptor signaling. The expression of GR was confirmed by western blots and q-PCR. Finally, we exposed breast cancer tumors bearing mice to a novel type of unpredictable social stress which well aligns with the psychological stressors experienced by breast cancer patients. Results: Our results indicate that GCs alone or in combination with 5FU enhanced cell proliferation (p&amp;lt;0.001) and reduced apoptosis, whereas RU-486, which antagonizes the action of GR, restored the apoptosis sensitivity of the GCs treated cells. SCNE minimized the effects of CGs. Currently, we are investigating the impact of unpredictable social environment as a chronic stressor on the growth of xenografted breast cancers in nude mice. Conclusions: Our study suggests that co-treatment of GCs protected breast cancer cells from 5FU-induced apoptosis, however utilizing SCNE may lessen the antagonizing effects of GCs. We cannot rule out the possibility that GCs may enhance resistance to chemotherapeutic drugs by modifying inflammation, angiogenesis or cell migration. Therefore, our current studies are aimed at investigating the possible pathways mediating GCs induced resistance to therapy in vitro and in vivo. Our ultimate goal is to elucidate the molecular mechanisms of GCs mediated inhibition of chemotherapy-induced cell death thereby proposing the ways of reversing this process. The literature suggests that around 35-45 % of cancer patients experience a significant level of stress which manifests in elevated production of natural GC cortisol. Furthermore, given that GCs are widely accepted as an adjuvant treatment during chemotherapy or radiotherapy for reducing side effects, it is critical to investigate the conditions upon which they exert either pro-apoptotic or anti-apoptotic action in different cancer types. Although more data is needed, our findings imply careful consideration for the profligate use of GCs combination therapy in the treatment of cancer patients. Citation Format: Kristina Andrijauskaite. Reducing the effects of glucocorticoids on breast cancer outcome in-vitro and in-vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4118.