Hormonal factors and pancreatic cancer risk in women: The <scp>M</scp>almö <scp>D</scp>iet and <scp>C</scp>ancer <scp>S</scp>tudy

Andersson, Gustav; Borgquist, Signe; Jirström, Karin

doi:10.1002/ijc.31302

Cited by 36 publications

(38 citation statements)

References 49 publications

(99 reference statements)

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“… 1 , 2 , 13 Consistent with this, use of estradiol-containing oral contraceptives and history of multiple pregnancies, which correlate with high estrogen exposure, are both associated with decreased PDAC risk. 14 , 15 , 16 Further supporting the idea that PDAC is influenced by estrogen are human clinical trials showing that tamoxifen, which is a GPER agonist, extends survival in PDAC patients. 17 , 18 These data, coupled with a lack of clear evidence that nuclear estrogen receptors are expressed or functional in PDAC, 19 and our RNAseq data ( Supplementary Data ) showing an absence of transcript for both of the classic estrogen receptors (ERα/ERβ) led us to test whether GPER activity inhibits PDAC.…”

mentioning

confidence: 90%

Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma

Natale

Pitarresi

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Pharmacologic activation of the G protein-coupled estrogen receptor (GPER) has been shown to inhibit multiple cancer types. Here we demonstrate that activation of GPER inhibits models of pancreatic ductal adenocarcinoma (PDAC), and that activation of GPER has combinatorial effects with immune checkpoint inhibitors. 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.

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confidence: 90%

Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma

Natale

Pitarresi

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Whilst the role of female hormone signaling in established pancreatic adenocarcinomas remains unclear, several studies, including research from our group, have suggested an inverse relationship between exogenous and endogenous female sex hormones and risk of pancreatic cancer [18–26]. Contrasting findings have however been presented by others [23, 25, 27–31].…”

Section: Introductionmentioning

confidence: 84%

Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma

et al. 2019

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BackgroundTamoxifen treatment has previously been reported to confer life-prolonging effects in patients with advanced pancreatic cancer, and most evidently so in women. None of these trials did however include biomarkers, and the relevance of female hormone signaling in pancreatic or other periampullary adenocarcinoma remains largely unexplored. The aim of this study was to examine the extent and potential clinical significance of estrogen receptor-α (ER) and progesterone receptor (PR) expression in pancreatic and other periampullary cancers.MethodsER and PR expression was examined using immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, with long-term clinical follow-up. Non-parametric and Chi square tests were applied to examine the associations of stromal ER and PR expression with patient and tumor characteristics. Kaplan-Meier analysis and log rank test were applied to illustrate survival differences in relation to ER and PR expression. Cox regression proportional hazards models were applied to examine the associations between investigative factors and risk of death and recurrence, and to test for interactions between KRAS mutation status and hormone receptor expression in relation to survival.ResultsExpression of both ER and PR was more frequent in the tumor-associated stroma than in the epithelium. A significant prognostic interaction, independent of tumor morphology, was found between stromal PR expression and KRAS mutation status in relation to both overall and recurrence-free survival (pinteraction = 0.026 and pinteraction = 0.005), in particular in women (pinteraction = 0.002 and pinteraction = 0.005). Specifically, stromal PR expression was associated with a prolonged survival in patients with KRAS-mutated tumors, whereas the opposite was seen for KRAS wild-type tumors. The prognostic value of ER positivity was limited to the subgroup of women with tumors of pancreatic origin.ConclusionsThese results demonstrate that stromal PR rather than ER expression, together with KRAS mutation status, provides long-term prognostic information in patients with periampullary adenocarcinoma. Further study into the mechanistic basis for these observations may unveil important clues to the pathogenesis of these cancers and open up for the discovery of novel treatment options.

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“…As with many cancers, women have lower PDAC incidence and more favorable outcomes than men, suggesting that estrogen may suppress PDAC (1,2,13). Consistent with this, use of estradiol containing oral contraceptives, and history of multiple pregnancies, which correlates with high estrogen exposure, are both associated with decreased PDAC risk (14)(15)(16). Further supporting the idea that PDAC is influenced by estrogen are human clinical trials showing that tamoxifen, which is a GPER agonist, extends survival in PDAC patients (17,18).…”

Section: Introductionmentioning

confidence: 87%

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

Natale

Dentchev

et al. 2018

Preprint

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AbstractFemale sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, 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. 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 many different cancer types.

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Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

Cited by 36 publications

References 49 publications

Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma

Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma

Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma

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

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