Abstract
Estrogen receptors are important regulators of the growth of breast tumors. Three different receptors for estrogens have been identified in breast tumors, two nuclear receptors, ERα and ERβ, and a G-protein coupled estrogen receptor 1 (GPER) that initiates non-genomic effects of estrogens in the cytosol. Recent findings show that the stimulation of cytoplasmic ERα and ERβ also triggers non-genomic signaling pathways. The treatment of breast cancer with anti-estrogens depends on the presence of ERα. About 40% of all breast cancers, however, do not express ERα. One subgroup of these tumors overexpress Her-2, another important group is designated as triple-negative breast cancer, as they neither express ERα, nor progesterone receptors, nor do they overexpress Her-2. This review addresses the signaling of ERβ and GPER in ERα-negative breast tumors. In addition to the well-established EGF-receptor transactivation pathways of GPER, more recent findings of GPER-dependent activation of FOXO3a, the Hippo-pathway, and HOTAIR-activation are summarized.
Highlights
Reviewed by: Pia Giovannelli, Università degli Studi della Campania Luigi Vanvitelli, Italy Marzia Di Donato, Università degli Studi della Campania Luigi Vanvitelli Caserta, Italy
Three different receptors for estrogens have been identified in breast tumors, two nuclear receptors, estrogen receptor α (ERα) and ERβ, and a G-protein coupled estrogen receptor 1 (GPER) that initiates non-genomic effects of estrogens in the cytosol
This review addresses the signaling of ERβ and GPER in ERα-negative breast tumors
Summary
In particular 17β-estradiol, exert biological effects in a wide variety of tissues. This receptor is a designated estrogen receptor α (ERα) in order to distinguish it from ERβ, which was discovered later Both receptors are ligand-activated transcription factors that act by binding to DNA in the nucleus. The C-domain that shares a 95% identity in amino acid sequence in both receptors is responsible for specific DNA-binding to promoters of the target genes. The estrogen-bound receptors enter the nucleus and bind with their C-domain to the estrogen-responsive elements (ERE), specific DNA-sequences of the promoters of target genes (Figure 1A). The activated RNA-polymerase synthesizes the m-RNA of the estrogen-dependent target genes and these mRNAs are exported from the nucleus to the ribosomes where they are translated to proteins These processes are called genomic effects of estrogen and require minutes to hours until they are completed [5]. The most important characteristics that distinguish genomic estrogen effects from the fast non-genomic effects is the fact that the genomic effects are inhibitable by inhibitors of RNA-polymerases like cycloheximide and actinomycin D
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