The “busy life” of unliganded estrogen receptors

Abstract

Understanding of the role of estrogen receptors (ERα and ERβ) in the pathophysiology of breast cancer (BC) has considerably increased in last decades. Despite sharing a similar structure, these two transcription factors often exert opposite roles in BC. In addition, it has been shown that their transcriptional activity is not strictly associated to ligand activation and that unliganded ERs are able to "have a life on their own." This appears to be mainly due to ligand-independent mechanisms leading to ERs PTMs or to their recruitment to specific protein complexes, dependent on cellular context. Furthermore, a significant unliganded ER activity, probably independent by the activation of other pathways, has been recently reported to affect gene transcription, microRNA expression, and downstream proteome. In this review, we describe recent findings on nuclear and cytoplasmic unliganded ERα and ERβ activity. We focus on functional genomics, epigenomics, and interaction proteomics data, including PTM induced by ERs-modulated miRNAs in the BC context. A better comprehension of the molecular events controlled by unliganded ERs activity in BC pathogenesis is crucial since it may impact the therapeutic approach to the initial or acquired resistance to endocrine therapies, frequently experienced in the treatment of BC.

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

“…In the absence of ligand, much of WT ERα, as well as that of other NR superfamily members, are bound by heat shock proteins, 4 an interaction that protects them from proteolysis and from which they can be released in an active form by ligand binding. Even without ligand, however, WT ERα may still regulate some genes and cellular functions, often through post-transcriptional modifications 37,38 that respond to other growth-regulating signaling systems, such as epidermal or insulin-like growth factors 39–42 . Also, the estrogen receptor does not work in isolation, and alterations in the levels and nature of associated and interacting factors—coregulators, other transcription factors, modifiers of the epigenome, post-translational modifications, cell-signaling pathways, the ERβ subtype 43 —can all modify how breast cancer will respond to hormone deprivation and antiestrogen treatments and lead to ligand-independent activation.…”

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…However, the previous report only screened very few members of the LDLR family during osteoblastic differentiation. Binding of estrogens to the receptors in the nucleus stimulates transcription of target genes resulting from direct interactions of the receptor proteins with DNA or from interactions with other transcription factors (34). However, there is no report regarding the expression of ApoE receptors mRNA induced by estrogen during osteoblast differentiation in vitro.…”

High Estrogen Receptor β Expression Is Prognostic among Adjuvant Chemotherapy–Treated Patients—Results from a Population-Based Breast Cancer Cohort

“…This may be explained by the shift of ERb transcriptional binding sites that occurs in the absence of ERa (25) and was recently discussed in a review and meta-analysis (26). Another tentative mechanistic explanation may be the more pronounced ligand-independent actions and basal activity of ERb compared with that of ERa (27). Previous results from this cohort suggested that the prognostic role of AR in breast cancer was dependent on the ERa status of the tumor (20).…”