Defining mechanisms of glucocorticoid receptor activity in breast, prostate, and ovarian cancer

Introduction: In prior work, my laboratory focused on identifying novel mechanisms of therapy resistance and progression in breast, prostate, and ovarian cancer. Several approaches led us and others to the discovery that glucocorticoid receptor (GR)–specific transcriptional regulation of gene expression in epithelial tumor cells with high GR expression and/or GR activity plays a master regulatory role in solid tumor biology.

Background: Glucocorticoid receptor (GR), a member of the nuclear hormone receptor family, appears to have highly context-dependent biological activity depending on additional hormone receptor activity.  For example, we have found that in triple-negative BC (TNBC, i.e. lacking HER2 as well as estrogen and progesterone receptors) GR induces cell survival and oncogenic gene expression independently of estrogen receptor (ER), while in ER+ BC, GR activity can coordinately modulate ER differentiation genes and simultaneously inhibit ER proliferative gene expression. Analogously, in androgen receptor (AR)-sensitive prostate cancer (PC), GR-mediated suppression of AR proliferative activity can occur. However, if AR is inhibited (e.g. by castration and enzalutamide), increased GR-mediated expression and activity evolve to become highly oncogenic. Finally, we have discovered that GR activity in ovarian cancer (OvCa) can inhibit chemotherapy sensitivity and is associated with an earlier probability of relapse in Stage I-III optimally treated patients (i.e. debulking surgery and chemotherapy). Taken together, our findings suggest that GR is a master regulator of gene expression pathways in multiple tumor types through both direct transcriptional and indirect (via active chromatin remodeling and resultant crosstalk with other receptors/transcription factors) mechanisms. Moreover, the molecular context of GR activity is critically important for approaching its therapeutic potential in the context of cancer prevention and therapy.

Rationale: Understanding mechanisms whereby glucocorticoid receptor (GR) regulates pre-malignant and malignant transcriptional networks will inform more effective prevention and treatment of breast, prostate, and ovarian cancers. Of note, highly GR-specific modulators (non-steroidal small molecule ligands) are currently under early-phase clinical evaluation for both cancer and metabolic disorders.  Thus, the next several years will be critical for expanding our understanding of GR activity in tumor evolution and therapy, as well as understanding the concurrent role of GR modulation in the tumor microenvironment. The iterative process of early clinical trial data interpretation and experimental lab data addressing basic GR function in targeted cancers (the focus of this application) is crucial to benefit cancer patients. While here we focus on understanding tumor cell-intrinsic GR biology, the results will also inform the field as to how GR modulation alters the expression of tumor cell surface and secreted proteins, thereby influencing the tumor-associated immune repertoire and microenvironment. Likewise, understanding GR function in the tumor immune microenvironment is a burgeoning field that will further inform our work.

Project 1: Identification of GR-mediated anti-proliferative mechanisms in constitutively active ER+ breast cancer (BC).

Project 2: Determining how GR transcriptional activity evolves before and following castration resistance in advanced human prostate cancer.

Project 3: Determining common GR-mediated transcriptional pathways expressed in high-grade ovarian cancer (OvCa) and associated with chemotherapy resistance.

Project 4: Investigating epigenetic mechanisms of GR-mediated physiological stress signaling that contribute to the etiology and biology of breast, prostate, and ovarian cancer.

Project 5: Investigating mechanisms by which tumor cell-intrinsic GR activity modulates the immune microenvironment of breast, prostate, and ovarian cancer.