Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Abstract

Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.

Clinical candidate and genistein analogue AXP107‐11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein‐coupled estrogen receptor signaling

“…GPER1 has been implicated in cell proliferation in various other tumors, and its ligand was recently demonstrated to be efficacious for treatment of melanoma in mice models . Genistein activates GPER1 with an EC 50 of 133 nmol/L .…”

Human scalp hair: Modulation by various factors and hormones do estrogens inhibit or stimulate—A perplexing perspective

“…However, information on GPR30 or GPER in hair follicles is lacking especially in light of the well‐known beneficial effects this receptor has in inhibiting breast cancer . However, the nonclassical estrogen signaling via GPER has been reported to inhibit melanoma . In this mechanism, GPER is activated by high 17β‐estradiol levels during pregnancy that induced c‐Myc protein degradation (via PKA) that slowed tumor growth by inhibiting the immune suppressive proteins (including PD‐L1) .…”

“…29 In this mechanism, GPER is activated by high 17β-estradiol levels during pregnancy that induced c-Myc protein degradation (via PKA) that slowed tumor growth by inhibiting the immune suppressive proteins (including PD-L1). 29 In general, the GPR30 or GPER cellular/molecular mechanisms also involve ERK and AKT signaling pathways that in turn influence various gene transcription elements. [27][28][29][30] Thus, much more is known about the expression and molecular (Figure 1).…”

“…29 In general, the GPR30 or GPER cellular/molecular mechanisms also involve ERK and AKT signaling pathways that in turn influence various gene transcription elements. [27][28][29][30] Thus, much more is known about the expression and molecular (Figure 1). These reports suggest selective 17β-estradiol and other hormone actions via ERs that may involve systemic and/ or locally synthesized steroid hormone, autocrine, intracrine, paracrine, or other signaling mechanisms that remain to be elucidated.…”

Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

“…A growing body of evidence suggests that nonclassical estrogen signaling through the G protein-coupled estrogen receptor (GPER) may be tumor suppressive, including in some cancers that are not traditionally considered sex hormone responsive, such as adrenocortical carcinoma, non-small cell lung cancer, colon carcinoma, osteosarcoma, and cutaneous melanoma (4)(5)(6)(7)(8)(9). Consistent with this, we recently showed that systemic administration of a specific small molecule synthetic GPER agonist, named G-1 (10), in mice with therapy-resistant syngeneic melanoma, induced differentiation in tumor cells that inhibited proliferation and rendered tumors more responsive to αPD-1 immune-checkpoint blockade (8). GPER is expressed in many tissues (11) and signaling downstream of GPER is mediated by ubiquitous cellular proteins that mediate cAMP signaling.…”