Abstract
GPR30, also known as GPER, has been suggested to mediate rapid effects induced by estrogens in diverse normal and cancer tissues. Hypoxia is a common feature of solid tumors involved in apoptosis, cell survival, and proliferation. The response to low oxygen environment is mainly mediated by the hypoxia-inducible factor named HIF-1α, which activates signaling pathways leading to adaptive mechanisms in tumor cells. Here, we demonstrate that the hypoxia induces HIF-1α expression, which in turn mediates the up-regulation of GPER and its downstream target CTGF in estrogen receptor-negative SkBr3 breast cancer cells and in HL-1 cardiomyocytes. Moreover, we show that HIF-1α-responsive elements located within the promoter region of GPER are involved in hypoxia-dependent transcription of GPER, which requires the ROS-induced activation of EGFR/ERK signaling in both SkBr3 and HL-1 and cells. Interestingly, the apoptotic response to hypoxia was prevented by estrogens through GPER in SkBr3 cells. Taken together, our data suggest that the hypoxia-induced expression of GPER may be included among the mechanisms involved in the anti-apoptotic effects elicited by estrogens, particularly in a low oxygen microenvironment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Hypoxia / drug effects
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Cell Hypoxia / genetics
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Cell Line, Tumor
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Estrogens / pharmacology
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / metabolism*
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Mammary Neoplasms, Animal / pathology
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Mice
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Receptors, Estrogen
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Receptors, G-Protein-Coupled / biosynthesis*
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Receptors, G-Protein-Coupled / genetics
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Response Elements / genetics
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Estrogens
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GPER1 protein, human
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Muscle Proteins
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Neoplasm Proteins
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Receptors, Estrogen
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Receptors, G-Protein-Coupled