GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer

Arias-Pulido, Hugo; Royce, Melanie; Gong, Yun; Joste, Nancy E.; Lomo, Lesley; Lee, Sang Joon; Chaher, Nabila; Verschraegen, Claire F.; Lara, Jonathan F.; Prossnitz, Eric R.; Cristofanilli, Massimo

doi:10.1007/s10549-009-0631-7

Cited by 74 publications

(71 citation statements)

References 34 publications

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“…The cross-talk between GPER-1 and EGFR is associated with activation of completely different signalling pathways [5,6,23] and could be responsible for the observed difference in survival rates. In agreement with the results obtained by us in the present study we have recently found that GPER-1 is associated with better patient survival in breast cancer patients [18] and have been recently confirmed for inflammatory breast cancer [24]. In accordance to expressional analyses, in vitro studies revealed controversial results regarding cellular functions of GPER-1.…”

Section: Discussionsupporting

confidence: 92%

GPER-1 acts as a tumor suppressor in ovarian cancer

Seiz¹,

Ignatov²,

Weißenborn³

et al. 2014

Geburtshilfe Frauenheilkd

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Background: It is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression. This study was conducted to evaluate the GPER-1 expression in ovarian cancer and its correlation with progression. Its function was tested in vitro in ovarian cancer cells. Patients and methods: GPER-1 expression was analyzed by immunohistochemistry in 35 benign ovarian tumors, 35 tumors of low-malignant potential and in 124 ovarian cancers. GPER-1 expression was correlated to the prospectively evaluated disease-free survival of ovarian cancer patients. We also tested GPER-1 expression in ovarian cancer cells and the effect of GPER-1 stimulation on cell growth. Results: GPER-1 expression was significantly lower in ovarian cancer tissue than in benign and low-malignant ovarian tumors. GPER-1 expression was observed in 83.1% of malignant tumors and was higher in early stage cancers and tumors with high histological differentiation. GPER-1 expression was associated with favourable clinical outcome. The difference in 2-year disease-free survival by GPER-1 expression was significant, 28.6% for GPER-1 negative and 59.2% for GPER-1 positive cases (p = 0.002). GPER-1 expression was observed in SKOV-3 and OVCAR-3 ovarian cancer cell lines. G-1, a selective GPER-1 agonist, suppressed proliferation of the two cell types via inhibition of cell cycle progression in G2/M phase and stimulation of caspase-dependent apoptosis. The blockade in G2/M phase was associated with increased expression of cyclin B1 and Cdc2 and phosphorylation of histone 3. Conclusion: GPER-1 emerges as a new tumor suppressor with unsuspected therapeutic potential for ovarian cancer.

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Section: Discussionsupporting

confidence: 92%

GPER-1 acts as a tumor suppressor in ovarian cancer

Seiz¹,

Ignatov²,

Weißenborn³

et al. 2014

Geburtshilfe Frauenheilkd

View full text Add to dashboard Cite

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“…Interestingly, high levels of expression of GPER1 in breast, endometrial, and ovarian tumors have been associated with a higher risk of developing metastatic disease and poor survival (Prossnitz & Barton 2011). Moreover, high levels of GPER1 were identified in inflammatory breast cancer (IBC), an aggressive and commonly hormone-independent form of breast cancer (Arias-Pulido et al 2010). Recently, the overexpression of GPER1 and its plasma membrane localization have been suggested to be critical events in breast cancer progression, whereas the lack of GPER1 in the plasma membrane was associated with excellent longterm prognosis in ESR1-positive (Sjöström et al 2014) tamoxifen-treated breast cancer.…”

Section: Introductionmentioning

confidence: 99%

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

Marco

Romeo

Vivacqua

et al. 2014

Endocrine-Related Cancer

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“…Moreover, in a previous extensive survey, GPR30 was found to be highly expressed and significantly associated with tumor size (>2 cm), with the presence of distant metastases and increased human EGFR-2 (HER-2)/neu expression (24). Likewise, in a recent study performed in the aggressive inflammatory breast cancer, the majority of tumors were GPR30 positive (25), indicating that GPR30 expression may be considered a predictor of an aggressive disease. Recently, we have found that one of the strongest genes induced through GPR30, such as CTGF, is required for both proliferation and migration in ER-negative SkBr3 breast cancer cells (26).…”

Section: Introductionmentioning

confidence: 87%

Nuclear Alternate Estrogen Receptor GPR30 Mediates 17β-Estradiol–Induced Gene Expression and Migration in Breast Cancer–Associated Fibroblasts

2010

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Fibroblasts are the principal cellular component of connective tissue and are associated with cancer cells at all stages of tumor progression. Structural and functional contributions of fibroblasts to the growth, survival, and invasive capacity of cancer cells are beginning to emerge. In breast carcinoma, ∼80% of stromal fibroblasts termed cancer-associated fibroblasts (CAF) are thought to manifest an activated phenotype that promotes cancer cell proliferation tumor growth at metastatic sites similar to the primary tumor. In this report, we show that CAFs respond to physiologic concentrations of 17β-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1. Notably, the E2 response is mediated by the alternate estrogen receptor GPR30, which interfaces with the epidermal growth factor receptor (EGFR) signaling pathway. In particular, E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter. Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. GPR30 was required for CAF proliferation and migration induced by E2. Our results provide important new mechanistic insights into how CAFs are stimulated by estrogen through a GPR30-mediated nuclear signaling pathway. More generally, they define estrogenic GPR30 signaling as a functionally important component of the tumor microenvironment. Cancer Res; 70(14); 6036-46. ©2010 AACR.

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GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer

Cited by 74 publications

References 34 publications

GPER-1 acts as a tumor suppressor in ovarian cancer

GPER-1 acts as a tumor suppressor in ovarian cancer

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

Nuclear Alternate Estrogen Receptor GPR30 Mediates 17β-Estradiol–Induced Gene Expression and Migration in Breast Cancer–Associated Fibroblasts

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