GPER‐induced signaling is essential for the survival of breast cancer stem cells

Chan, Yu‐Tzu; Lai, Alan Chuan‐Ying; Lin, Ruey‐Jen; Wang, Yahui; Wang, Yi‐Ting; Chang, Wen‐Wei; Wu, Hsin‐Yi; Lin, Yu‐Jen; Chang, Wen-Yi; Wu, Jun; Yu, Jyh‐Cherng; Chen, Yu‐Ju; Yu, Alice L.

doi:10.1002/ijc.32588

Cited by 41 publications

(43 citation statements)

References 49 publications

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“…Protein phosphorylation is central to the understanding of downstream signaling pathways responsible for regulating stem cell functions. Quantitative phosphoproteomics has been used to study global signaling events in pluripotent, and cancer stem cells and new therapeutic targets have accordingly been proposed ( 59 – 62 ). To our knowledge, however, it has not been used before to assess the impact of inflammation on stem cell biology.…”

Section: Discussionmentioning

confidence: 99%

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions

Albuquerque‐Souza

Schulte

Chen³

et al. 2020

Front. Immunol.

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Maresin-1 (MaR1) and Resolvin E1 (RvE1) are specialized pro-resolving lipid mediators (SPMs) that regulate inflammatory processes. We have previously demonstrated the hard and soft tissue regenerative capacity of RvE1 in an in vivo model of the periodontal disease characterized by inflammatory tissue destruction. Regeneration of periodontal tissues requires a well-orchestrated process mediated by periodontal ligament stem cells. However, limited data are available on how SPMs can regulate the regenerative properties of human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. Thus, we measured the impact of MaR1 and RvE1 in an in vitro model of hPDLSC under stimulation with IL-1β and TNF-α by evaluating pluripotency, migration, viability/cell death, periodontal ligament markers (α-smooth muscle actin, tenomodulin, and periostin), cementogenic-osteogenic differentiation, and phosphoproteomic perturbations. The data showed that the pro-inflammatory milieu suppresses pluripotency, viability, and migration of hPDLSCs; MaR1 and RvE1 both restored regenerative capacity by increasing hPDLSC viability, accelerating wound healing/migration, and up-regulating periodontal ligament markers and cementogenicosteogenic differentiation. Protein phosphorylation perturbations were associated with the SPM-induced regenerative capacity of hPDLSCs. Together, these results demonstrate that MaR1 and RvE1 restore or improve the regenerative properties of highly specialized stem cells when inflammation is present and offer opportunities for direct pharmacologic treatment of lost tissue integrity.

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Section: Discussionmentioning

confidence: 99%

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions

Albuquerque‐Souza

Schulte

Chen³

et al. 2020

Front. Immunol.

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“…Several observations strongly support that it is. First, GPER is required for the survival of xenograft-derived cancer stem cells and metastatic disease (59). Second, in breast cancer cells, GPER integrates assembly of the fibronectin matrix (60) with the release of EGF (61); thus satisfying two basic requirements or cellular survival: attachment to the extracellular matrix and responsiveness to growth factors.…”

Section: Gper In Metabolic Disease and Cancermentioning

confidence: 99%

Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function

Rouhimoghadam

Salem

et al. 2020

Front. Endocrinol.

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Estrogens exert their physiological and pathophysiological effects via cellular receptors, named ERα, ERβ, and G-protein coupled estrogen receptor (GPER). Estrogen-regulated physiology is tightly controlled by factors that regulate estrogen bioavailability and receptor sensitivity, while disruption of these control mechanisms can result in loss of reproductive function, cancer, cardiovascular and neurodegenerative disease, obesity, insulin resistance, endometriosis, and systemic lupus erythematosus. Restoration of estrogen physiology by modulating estrogen bioavailability or receptor activity is an effective approach for treating these pathological conditions. Therapeutic interventions that block estrogen action are employed effectively for the treatment of breast and prostate cancer as well as for precocious puberty and anovulatory infertility. Theoretically, treatments that block estrogen biosynthesis should prevent estrogen action at ERs and GPER, although drug resistance and ligand-independent receptor activation may still occur. In addition, blockade of estrogen biosynthesis does not prevent activation of estrogen receptors by naturally occurring or man-made exogenous estrogens. A more complicated scenario is provided by anti-estrogen drugs that antagonize ERs since these drugs function as GPER agonists. Based upon its association with metabolic dysregulation and advanced cancer, GPER represents a therapeutic target with promise for the treatment of several critical health concerns facing Western society. Selective ligands that specifically target GPER have been developed and may soon serve as pharmacological agents for treating human disease. Here, we review current forms of estrogen therapy and the implications that GPER holds for these therapies. We also discuss existing GPER targeted drugs, additional approaches towards developing GPER-targeted therapies and how these therapies may complement existing modalities of estrogen-targeted therapy.

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“…In addition, the GPER-1/EGFR signaling axis mediates the expression of cell cycle regulatory genes in cancer-associated fibroblasts derived from breast cancer patients, favoring tumor progression (40). It has recently been shown that stimulation with tamoxifen, activates GPER-1, improving breast cancer stem cells viability and stemness and BAD phosphorylation, event that seems to be an alternative survival mechanism for these cells (51).…”

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confidence: 99%

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

et al. 2020

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GPER-1 is a novel membrane sited G protein-coupled estrogen receptor. Clinical studies have shown that patients suffering an estrogen receptor a (ERa)/GPER-1 positive, breast cancer have a lower survival rate than those who have developed ERa-positive/GPER-1 negative tumors. Moreover, absence of GPER-1 improves the prognosis of patients treated with tamoxifen, the most used selective estrogen receptor modulator to treat ERapositive breast cancer. MCF-7 breast cancer cells were continuously treated with 1,000 nM tamoxifen for 7 days to investigate its effect on GPER-1 protein expression, cell proliferation and intracellular [Ca 2+ ]i mobilization, a key signaling pathway. Breast cancer cells continuously treated with tamoxifen, exhibited a robust [Ca 2+ ]i mobilization after stimulation with 1,000 nM tamoxifen, a response that was blunted by preincubation of cells with G15, a commercial GPER-1 antagonist. Continuously treated cells also displayed a high [Ca 2+ ]i mobilization in response to a commercial GPER-1 agonist (G1) and to estrogen, in a magnitude that doubled the response observed in untreated cells and was almost completely abolished by G15. Proliferation of cells continuously treated with tamoxifen and stimulated with 2,000 nM tamoxifen, was also higher than that observed in untreated cells in a degree that was approximately 90% attributable to GPER-1. Finally, prolonged tamoxifen treatment did not increase ERa expression, but did overexpress the kinin B1 receptor, another GPCR, which we have previously shown is highly expressed in breast tumors and increases proliferation of breast cancer cells. Although we cannot fully extrapolate the results obtained in vitro to the patients, our results shed some light on the occurrence of drug resistance in breast cancer patients who are ERa/GPER-1 positive, have been treated with tamoxifen and display low survival rate. Overexpression of kinin B1 receptor may explain the increased proliferative response observed in breast tumors under continuous treatment with tamoxifen.

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GPER‐induced signaling is essential for the survival of breast cancer stem cells

Cited by 41 publications

References 49 publications

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions

Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

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