Abstract
Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.
Highlights
Estrogen, the female sex hormone that is best known for its role in female reproduction and mammary gland development, plays a role in many other physiological systems, including metabolism and the cardiovascular and immune systems [1,2]
Co-treatment with an anti-PD-1 antibody and G-1 shrank tumors, and significantly improved survival of melanoma-bearing mice. They identified that activation of G protein-coupled estrogen receptor (GPER) by G-1, in melanoma xenografts, induces a decrease in c-Myc levels, which results in decreased cell surface expression of programmed cell death ligand-1 (PD-L1) and increased cell surface levels of human leukocyte antigen (HLA), which together lead to improved immune recognition of melanoma tumor cells
A pro-migratory role for GPER in breast cancer-associated fibroblasts (CAFs) was demonstrated as a result of the hypoxia-driven expression of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and CTGF, with enhanced invasion of breast cancer cells occurring in a GPER/CTGF-dependent manner [107]
Summary
The female sex hormone that is best known for its role in female reproduction and mammary gland development, plays a role in many other physiological systems, including metabolism and the cardiovascular and immune systems [1,2]. ERα is the main driver of the majority (~70%) of primary breast cancers, GPER, over the past decade, has gained interest as a potential contributor to the development of endocrine resistance in the breast cancer relapse setting [9,17,18]. This is in part due to observations that tamoxifen, a standard-of-care drug for ERα-positive breast cancers, cross-activates GPER [19,20]. We discuss the direct roles of GPER in several cancers, as well as indirect roles based on obesity and metabolism- and immune-related stromal cells, suggesting multiple therapeutic roles for GPER-targeted drugs in the treatment of cancer
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