Abstract P6-04-27: Natural and synthetic glucocorticoids induce therapy resistance in breast cancer in vitro
Authors: Kristina Andrijauskaite, Michael Wargovich
Journal: Cancer Research (2020)

Abstract BACKGROUND: Research indicates that chronic psychological stress, mediated by the excessive release of glucocorticoid (GC) cortisol, may play a role in cancer progression and patient survival. Thus, synthetic GCs, such as dexamethasone, are widely used in conjugation with cancer therapy as anti-inflammatory and immunosuppressive agents. Surprisingly, recent evidence suggest that GCs can induce therapy-resistance in solid tumors, although the precise mechanisms are not well defined. Therefore, there is an urgent need for both clinical and detailed mechanistic studies elucidating the role of GCs in cancer treatment. The goal of this study was to investigate the role of natural and synthetic GCs on resistance to cytotoxic therapy in breast cancer in vitro. METHODS: We either pre-treated or co-treated human breast cancer cells (MCF7, 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) for 48-96 hours. We performed cell viability, proliferation, cell cycle and apoptosis assays. Thus, we used the glucocorticoid receptor (GR) antagonist (RU-486) to assess the role of GC receptor signaling. The expression of GR was confirmed by western blots. We have also assessed the expression of pro-inflammatory markers. RESULTS: Our results indicate that GCs alone or in combination with 5FU enhanced cell proliferation, especially in MDA-MB-231 cells (p&amp;lt;0.01). Furthermore, GCs also modulated cell cycle and apoptosis. However, the glucocorticoid antagonist RU-486 restored the apoptosis sensitivity of the GCs treated cells. Finally, we observed that GR activation with a clinically relevant doses of dexamethasone and cortisol affected the expression of pro-inflammatory cytokines. CONCLUSIONS: Our study suggests that in contrast to the pro-apoptotic effect of GCs in lymphoid cells, co-treatment of GCs protected breast cancer cells from 5FU-induced apoptosis. Given our results, it is difficult to conclude whether the primary detrimental effect of GCs is on cell viability and apoptosis. We cannot rule out the possibility that GCs my 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. Our ultimate goal is to elucidate the molecular mechanisms of the glucocorticoids mediated inhibition of chemotherapy-induced cell death thereby proposing the ways of reversing this process. The literature suggest that around 35-45 % of cancer patients experience 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, Michael Wargovich. Natural and synthetic glucocorticoids induce therapy resistance in breast cancer in vitro [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-27.