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Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

Minas Sakellakis¹, Laura Jacqueline Flores²

¹Department of Genitourinary Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States.

|July 22, 2022

Abstract:

Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR.

Insights

Glucocorticoid receptor (GR) signaling in prostate cancer can promote castration resistance and tumor survival, even undermining anti-cancer treatments. Understanding GR activity is key for optimizing glucocorticosteroid use and targeting its pro-tumor effects.

Area of Science:

Endocrinology
Oncology
Molecular Biology

Background:

Glucocorticoids exert diverse effects in cancer via the glucocorticoid receptor (GR).
In prostate cancer, GR signaling can influence castration resistance and tumor cell survival.
GR and androgen receptor (AR) pathways interact, with implications for treatment resistance.

Purpose of the Study:

To elucidate the multifaceted roles of GR in prostate cancer.
To understand how GR signaling impacts treatment response, including resistance to anti-androgen therapies.
To identify strategies for targeting GR's protumorigenic effects.

Main Methods:

Analysis of GR and AR transcriptomes and cistromes in prostate cancer cells.
Investigation of GR signaling under enzalutamide treatment.
Assessment of GR's impact on gene expression related to proliferation and survival.

Main Results:

GR signaling can promote castration resistance by activating a subset of AR-target genes.
GR activation can enhance prostate cancer cell survival and undermine anti-cancer treatments.
GR and AR share overlapping but distinct functions and target genes.

Conclusions:

GR plays a complex role in prostate cancer, contributing to both resistance and survival.
Optimal use of glucocorticosteroids in prostate cancer requires a full understanding of GR activity.
Targeting GR is crucial for overcoming treatment resistance and managing prostate cancer progression.

Read full analysis

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