Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary
Background & Aims: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despi...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20300667 |
| _version_ | 1818134106934870016 |
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| author | Christopher A. Natale Jinyang Li Jason R. Pitarresi Robert J. Norgard Tzvete Dentchev Brian C. Capell John T. Seykora Ben Z. Stanger Todd W. Ridky |
| author_facet | Christopher A. Natale Jinyang Li Jason R. Pitarresi Robert J. Norgard Tzvete Dentchev Brian C. Capell John T. Seykora Ben Z. Stanger Todd W. Ridky |
| author_sort | Christopher A. Natale |
| collection | DOAJ |
| description | Background & Aims: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors. Methods: Here we used murine syngeneic tumor models and human xenografts to determine that signaling through the nonclassic estrogen receptor G protein-coupled estrogen receptor (GPER) on tumor cells inhibits PDAC. Results: Activation of GPER with the specific, small molecule, synthetic agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically administered G-1 was well-tolerated in PDAC bearing mice, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors, independent of tumor stage. Conclusions: These data, coupled with the wide tissue distribution of GPER and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive and that arise in tissues outside of the reproductive system. |
| first_indexed | 2024-12-11T09:03:21Z |
| format | Article |
| id | doaj.art-946b93cabff04f0896338d86cd960e53 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-11T09:03:21Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-946b93cabff04f0896338d86cd960e532022-12-22T01:13:41ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-01104868880.e1Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummaryChristopher A. Natale0Jinyang Li1Jason R. Pitarresi2Robert J. Norgard3Tzvete Dentchev4Brian C. Capell5John T. Seykora6Ben Z. Stanger7Todd W. Ridky8Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia; Linnaeus Therapeutics Inc, Philadelphia, PennsylvaniaPerelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PennsylvaniaPerelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PennsylvaniaPerelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PennsylvaniaPerelman School of Medicine, Department of Dermatology, University of Pennsylvania, PhiladelphiaPerelman School of Medicine, Department of Dermatology, University of Pennsylvania, PhiladelphiaPerelman School of Medicine, Department of Dermatology, University of Pennsylvania, PhiladelphiaPerelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PennsylvaniaPerelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia; Correspondence Address correspondence to: Todd W. Ridky, MD, PhD, Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104. fax: (215) 573-2143.Background & Aims: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors. Methods: Here we used murine syngeneic tumor models and human xenografts to determine that signaling through the nonclassic estrogen receptor G protein-coupled estrogen receptor (GPER) on tumor cells inhibits PDAC. Results: Activation of GPER with the specific, small molecule, synthetic agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically administered G-1 was well-tolerated in PDAC bearing mice, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors, independent of tumor stage. Conclusions: These data, coupled with the wide tissue distribution of GPER and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive and that arise in tissues outside of the reproductive system.http://www.sciencedirect.com/science/article/pii/S2352345X20300667Pancreatic Ductal AdenocarcinomaPDACG Protein-Coupled Estrogen ReceptorGPER |
| spellingShingle | Christopher A. Natale Jinyang Li Jason R. Pitarresi Robert J. Norgard Tzvete Dentchev Brian C. Capell John T. Seykora Ben Z. Stanger Todd W. Ridky Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary Cellular and Molecular Gastroenterology and Hepatology Pancreatic Ductal Adenocarcinoma PDAC G Protein-Coupled Estrogen Receptor GPER |
| title | Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary |
| title_full | Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary |
| title_fullStr | Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary |
| title_full_unstemmed | Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary |
| title_short | Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal AdenocarcinomaSummary |
| title_sort | pharmacologic activation of the g protein coupled estrogen receptor inhibits pancreatic ductal adenocarcinomasummary |
| topic | Pancreatic Ductal Adenocarcinoma PDAC G Protein-Coupled Estrogen Receptor GPER |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X20300667 |
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