Abstract 6281: Context dependent role of glucocorticoids in breast cancer

Abstract

Abstract Glucocorticoids bind to the transcription factor glucocorticoid receptor (GR) and regulate genes in response to cellular metabolism, inflammation, and stress. Although GR has been extensively evaluated in inflammation and metabolic diseases, its role as a therapeutic target in cancer has not been thoroughly studied. Results from studies with another member of the steroid receptor family, androgen receptor (AR), demonstrated that the AR is an oncogene in estrogen receptor (ER)-negative breast cancer, but a tumor suppressor in ER-positive breast cancer. We expected a comparable mechanism with GR in different breast cancer subtypes. In this study, we evaluated the role of GR in various breast cancer subtypes and discerned the mechanism of action. Six breast cancer cell lines and seven patient-derived xenografts (PDXs) were characterized by Western blot for their expression of GR, ER and AR. Proliferation assays were performed in cell lines with a dose-response of a synthetic glucocorticoid, dexamethasone. Subsequently, we performed xenograft studies in cell line xenografts (CDXs) and PDXs. GR was ubiquitously expressed in various cell lines and PDX models. Dexamethasone reduced cell proliferation in ER-positive models, while it increased the proliferation in ER-negative cell lines, suggesting that the GR might have a mechanism of action that is similar to AR. GR antagonist, mifepristone, reversed the effects of dexamethasone. CDX studies in an ER-positive cell line, MCF7 suggested that dexamethasone (10 mpk) inhibited the tumor growth significantly that was better than the standard of care fulvestrant. This result was confirmed in an ER positive PDX model HCI013. Study by Obradović et al, indicates that glucocorticoids have an oncogenic role and furthermore promote breast cancer metastasis in TNBC model thereby validating the subtype and context dependent role of the glucocorticoid receptor. We are currently exploring the mechanism of GR’s context-dependent tumor suppressor and oncogenic role in distinct breast cancer subtypes. Citation Format: Wendy Effah, Suriyan Ponnusamy, Sarah Asemota, Yekta Khosrosereski, Ramesh Narayanan. Context dependent role of glucocorticoids in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6281.