Estrogen Signaling in ERα-Negative Breast Cancer: ERβ and GPER

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.

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

“…T. pratense preparations contain large quantities of formononetin, and that compound was shown to reveal dosage-dependent estrogenic activity in MCF-7 cells [55]. Still, it should be taken into account that, as observed in the estrogenic activity assay, increased MCF-7 cell proliferation may result not only from the activation of estrogen receptors, but mediated signaling pathways as well [3,4].…”

“…Among other isoflavones with GPR30 agonist activity, coumestrol was also identified, which on the other hand is known as an antagonist of ERα and ERβ receptors. Thus, after its binding to GPR30 and the activation of signaling pathways in breast cancer cells, stimulation of proliferation could be observed [3].…”

“…The 17 β-estradiol molecule passively enters the cell through the plasma membrane, and after binding with ERs initiates different cellular processes, i.e., proliferation, differentiation and survival, via regulation of genes transcription after binding to the estrogen-responsive element (ERE) on the promotors of the ER target genes site, and modification of chromatin structure [2]. Despite the classical or genomic action of steroid receptors, they possess also non-genomic rapid activity via upstream interactions with signaling or scaffold proteins controlling cell cycle, proliferation, migration or nuclear exclusion of steroid receptors [3,4]. Through the direct interaction of ERα with proteins, activation of the Src-and PI3-kinase-dependent pathways occurs, which induces DNA synthesis and cytoskeleton changes in breast cancer MCF-7 cells in the absence of 17 β-estradiol.…”

“…Through the direct interaction of ERα with proteins, activation of the Src-and PI3-kinase-dependent pathways occurs, which induces DNA synthesis and cytoskeleton changes in breast cancer MCF-7 cells in the absence of 17 β-estradiol. Because ER location regulates the estradiol signaling output, specific targeting of the interaction between estrogen receptors and signaling effectors (like Src family tyrosine kinases involved in signaling transduction pathways) or nuclear export receptors (exportin/Crm1 protein involved in ER export form nuclei) antagonizes the proliferative rate of breast cancer cells [3,4]. Both ERα and ERβ proteins are expressed not only in many normal tissues, but also in cancers with motility and invasive properties [1].…”

Overview of Current Findings about the Role of Oestrogen Receptor α in Cancer Cell Signalling Pathways

“…Nejdůležitější skutečnost, která oba mechanizmy odlišuje a promítá se i do praxe, je možnost potlačit genomické účinky ERα pomocí inhibitorů RNA polymeráz, mezi které patří např. cykloheximid nebo aktinomycin D [4].…”