Human estrogen receptor α antagonists, part 2: Synthesis driven by rational design, in vitro antiproliferative, and in vivo anticancer evaluation of innovative coumarin-related antiestrogens as breast cancer suppressants

2021 ◽  
pp. 113869 ◽  
Author(s):  
Nezrina Kurtanović ◽  
Nevena Tomašević ◽  
Sanja Matić ◽  
Marina M. Mitrović ◽  
Danijela A. Kostić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Rational Design ◽  
Estrogen Receptor Α ◽  
Human Estrogen Receptor

scholarly journals Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity

2008 ◽  
Vol 40 (4) ◽  
pp. 173-184 ◽  
Author(s):  
Ross S Thomas ◽  
Naveed Sarwar ◽  
Fladia Phoenix ◽  
R Charles Coombes ◽  
Simak Ali
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Mitogen Activated Protein Kinase ◽  
Breast Cancer Patients ◽  
Independent Manner ◽  
Stimulation Of

Phosphorylation of estrogen receptor-α (ERα) at specific residues in transcription activation function 1 (AF-1) can stimulate ERα activity in a ligand-independent manner. This has led to the proposal that AF-1 phosphorylation and the consequent increase in ERα activity could contribute to resistance to endocrine therapies in breast cancer patients. Previous studies have shown that serine 118 (S118) in AF-1 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) in a ligand-independent manner. Here, we show that serines 104 (S104) and 106 (S106) are also phosphorylated by MAPK in vitro and upon stimulation of MAPK activity in vivo. Phosphorylation of S104 and S106 can be inhibited by the MAP-erk kinase (MEK)1/2 inhibitor U0126 and by expression of kinase-dead Raf1. Further, we show that, although S118 is important for the stimulation of ERα activity by the selective ER modulator 4-hydroxytamoxifen (OHT), S104 and S106 are also required for the agonist activity of OHT. Acidic amino acid substitution of S104 or S106 stimulates ERα activity to a greater extent than the equivalent substitution at S118, suggesting that phosphorylation at S104 and S106 is important for ERα activity. Collectively, these data indicate that the MAPK stimulation of ERα activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ERα at these sites may contribute to resistance to tamoxifen in breast cancer.

In vivo and in vitro phosphorylation of the human estrogen receptor

1995 ◽  
Vol 52 (2) ◽  
pp. 159-171 ◽  
Author(s):  
Steven F. Arnold ◽  
John D. Obourn ◽  
Matthew R. Yudt ◽  
Timothy H. Carter ◽  
Angelo C. Notides
Keyword(s):  
Estrogen Receptor ◽  
Human Estrogen Receptor

scholarly journals Role of estrogen receptor coregulators in endocrine resistant breast cancer

2021 ◽  
pp. 385-400
Author(s):  
Kristin A. Altwegg ◽  
Ratna K. Vadlamudi
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Therapy Resistance ◽  
Vital Role ◽  
In Vivo Studies ◽  
Scaffolding Proteins ◽  
Current State ◽  
Er Alpha

Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70-80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid hormone estrogen [17β-estradiol (E2)] plays a vital role both in the initiation and progression of BC. The E2-ERα mediated actions involve genomic signaling and non-genomic signaling. The specificity and magnitude of ERα signaling are mediated by interactions between ERα and several coregulator proteins called coactivators or corepressors. Alterations in the levels of coregulators are common during BC progression and they enhance ligand-dependent and ligand-independent ERα signaling which drives BC growth, progression, and endocrine therapy resistance. Many ERα coregulator proteins function as scaffolding proteins and some have intrinsic or associated enzymatic activities, thus the targeting of coregulators for blocking BC progression is a challenging task. Emerging data from in vitro and in vivo studies suggest that targeting coregulators to inhibit BC progression to therapy resistance is feasible. This review explores the current state of ERα coregulator signaling and the utility of targeting the ERα coregulator axis in treating advanced BC.

scholarly journals Comparative study of estrogen receptor α, β mRNA expressions of endometriosis and normal endometrium in women and analysis of potential synthetic anti-estrogens in silico

2018 ◽  
Vol 91 (2) ◽  
Author(s):  
Eldafira Eldafira ◽  
Abinawanto Abinawanto ◽  
Luthfiralda Sjahfirdi ◽  
Asmarinah Asmarinah ◽  
Purnomo Soeharso ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mrna Expression ◽  
Estrogen Receptor Α ◽  
Assay Method ◽  
Enzyme Linked Immunosorbent Assay ◽  
Normal Endometrium ◽  
Pcr Method ◽  
Genetic And Environmental Factors

Endometriosis is a multifactorial disease in which genetic and environmental factors interact causing its pathogenesis. The aim of this study was to investigate the expression pattern of estrogen receptor α (ERα) and β (ERβ) in endometriosis patients compared to normal endometrioum (n=18) as a control by using Quantitative Real Time PCR method. Moreover, we also measured serum estradiol levels of endometriosis patients in the proliferation phase of the menstrual cycle using the enzyme-linked immunosorbent assay method. The mRNA expression of ERβ was significantly higher in the endometriosis group compared to control, and the result of t-test showed that were significantly different (P<0.05). Overexpression of ERβ in endometriosis was likely to have other significant important impacts in the pathology of endometriosis that allowed ERβ to stimulate prostaglandin production in endometriosis tissue and cells. Estradiol content did not correlate with the ERα expression, and it is weakly correlated with ERβ mRNA expression. Molecular docking analysis showed that ERα and ERβ have different binding interactions with synthetic antiestrogens, whereas the best inhibitor was Ral2 to ERα and Aco1 to ERβ. Thus, both inhibitors could be used as leads in further investigation of ERα, ERβ inhibitory activities in vitro and in vivo.

scholarly journals Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells

2019 ◽  
Vol 5 (2) ◽  
pp. eaav5590 ◽  
Author(s):  
Giovanni Nassa ◽  
Annamaria Salvati ◽  
Roberta Tarallo ◽  
Valerio Gigantino ◽  
Elena Alexandrova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Gene Transcription ◽  
Apoptotic Cell ◽  
Estrogen Receptor Α ◽  
Cycle Arrest ◽  
H3k79 Methylation ◽  
Target Gene Transcription

Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor α (ERα) signaling, and ways to block ERα pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ERα in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ERα and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ERα levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy–resistant ERα-positive BCs.

scholarly journals The Human Estrogen Receptor-α Isoform hERα46 Antagonizes the Proliferative Influence of hERα66 in MCF7 Breast Cancer Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5474-5484 ◽  
Author(s):  
Graziella Penot ◽  
Christine Le Péron ◽  
Yohann Mérot ◽  
Eva Grimaud-Fanouillère ◽  
François Ferrière ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Growth ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Exact Function ◽  
Human Estrogen Receptor

The expression of two human estrogen receptor-α (hERα) isoforms has been characterized within estrogen receptor-α-positive breast cancer cell lines such as MCF7: the full-length hERα66 and the N terminally deleted hERα46, which is devoid of activation function (AF)-1. Although hERα66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hERα46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hERα46 is mainly expressed in the nucleus at relatively low levels, whereas hERα66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hERα46 accumulating within the nucleus. Although hERα46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G0/G1 phases. To gain further details on the influence of hERα46 on cell growth, we used PC12 estrogen receptor-α-negative cell line, in which stable transfection of hERα66 but not hERα46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hERα46 inhibits the hERα66-mediated estrogenic induction of all AF-1-sensitive reporters: c-fos and cyclin D1 as well as estrogen-responsive element-driven reporters. Our data indicate that this inhibition occurs likely through functional competitions between both isoforms. In summary, hERα46 antagonizes the proliferative action of hERα66 in MCF7 cells in part by inhibiting hERα66 AF-1 activity.

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