Abstract
The pleiotropic nature of oestradiol, the main oestrogen found in women, has been well described in the literature. Oestradiol is positioned to play a unique role since it can respond to environmental, genetic and non-genetic cues to affect genetic expression and cellular signalling. In breast cancer, oestradiol signalling has a dual effect, promoting or inhibiting cancer growth. The potential impact of oestradiol on tumorigenesis depends on the molecular and cellular characteristics of the breast cancer cell. In this review, we provide a broad survey discussing the cellular and molecular consequences of oestrogen signalling in breast cancer. First, we review the structure of the classical oestrogen receptors and resultant transcriptional (genomic) and non-transcriptional (non-genomic) signalling. We then discuss the nature of oestradiol signalling in breast cancer including the specific receptors that initiate these signalling cascades as well as potential outcomes, such as cancer growth, proliferation and angiogenesis. Finally, we examine cellular and molecular mechanisms underlying the dimorphic effect of oestrogen signalling in breast cancer.
Highlights
Oestrogens are steroid hormones that play key roles in growth, development, reproduction and maintenance of a diverse range of mammalian tissues
The DBD domain binds to the oestrogen response elements (EREs), which reside near the promoter or enhancer regions, and Abbreviations: Adora1, adenosine A1 receptor; AF, activation function; activation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase B; ALP, alkaline phosphatases; AMPK, AMP-activated protein kinase; Ang-1, angiopoietin-1; CXCR1, CXC receptor-1; DBD, DNA-binding domain; E1, oestrone; E2, 17β-oestradiol; E3, oestriol; Egr-1, early growth response protein 1; ERα, oestrogen receptor alpha; ERβ, oestrogen receptor beta; ERBB2, erythroblastic leukaemia viral oncogene homologue 2; ERE, oestrogen response element; ERK, extracellular-signal-regulated kinase; Ets1, v-ets avian erythroblastosis virus E26 oncogene homologue 1; FAK, focal adhesion kinase; FOS, FBJ murine osteosarcoma viral oncogene homologue; GATA1, GATA binding protein 1; GD3S, GD3 synthase; GPER1, G-protein-coupled oestrogen receptor 1
In addition to the wild type ER, there are multiple variant isoforms that originate by protein truncation or single amino acid mutations
Summary
Oestrogens are steroid hormones that play key roles in growth, development, reproduction and maintenance of a diverse range of mammalian tissues. E2 can influence expression of genes that do not harbour EREs in their promoter region by indirect transcriptional signalling In this case, instead of binding to DNA directly, they form protein–protein interactions with partner transcription factors. Non-transcriptional signalling usually involves direct association of ERs with target proteins in response to E2 stimulation This leads to activation of kinases, phosphatases and increases in ion fluxes across membranes. In addition to directly mediating IGF-I transcription by binding to ERE, ERα associates with IGF-I membrane receptor (IGF-IR) and activates MAP kinase cascades that influence ERα mediated gene transcription [32]. Another example of dual transcriptional and non-transcriptional action is the transcription of low-density lipoprotein receptor
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