scholarly journals Epithelial-mesenchymal plasticity determines estrogen receptor positive (ER+) breast cancer dormancy and reacquisition of an epithelial state drives awakening

2021 ◽  
Author(s):  
Aouad Patrik ◽  
Zhang Yueyun ◽  
Celine Stibolt ◽  
Mani Sendurai ◽  
Georgios Sflomos ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Therapeutic Potential ◽  
Lung Metastases ◽  
Disseminated Tumor Cells ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Cancer Dormancy ◽  
Latent Disease ◽  
Epithelial State

Estrogen receptor α-positive (ER+) breast cancers (BCs) represent more than 70% of all breast cancers and pose a particular clinical challenge because they recur up to decades after initial diagnosis and treatment. The mechanisms governing tumor cell dormancy and latent disease remain elusive due to a lack of adequate models. Here, we compare tumor progression of ER+ and triple-negative (TN) BC subtypes with a clinically relevant mouse intraductal xenografting approach (MIND). Both ER+ and TN BC cells disseminate already during the in situstage. However, TN disseminated tumor cells (DTCs) proliferate at the same rate as cells at the primary site and give rise to macro-metastases. ER+ DTCs have low proliferative indices, form only micro-metastases and lose epithelial characteristics. Expression of CDH1 is decreased whereas the mesenchymal marker VIM and the transcription factors, ZEB1/ZEB2, which control epithelial-mesenchymal plasticity (EMP) are increased. EMP is not detected earlier during ER+ BC development and not required for invasion or metastasis. In vivo, forced transition to the epithelial state through ectopic E-cadherin expression overcomes dormancy with increased growth of lung metastases. We conclude that EMP is essential for the generation of a dormant cell state and the development of latent disease. Targeting exit from EMP is of therapeutic potential.

scholarly journals Intraductal patient derived xenografts of estrogen receptor positive (ER+) breast cancer recapitulate the histopathological spectrum and metastatic potential of human lesions

2018 ◽  
Author(s):  
Maryse Fiche ◽  
Valentina Scabia ◽  
Laura Battista ◽  
Assia Treboux ◽  
Athina Stravodimou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Conflict Of Interest ◽  
Tumor Development ◽  
Metastatic Potential ◽  
Estrogen Receptor Α ◽  
Biological Properties ◽  
Breast Cancers

AbstractEstrogen receptor α positive (ER+) or “luminal” breast cancers were notoriously difficult to establish as patient-derived xenografts (PDXs). We and others recently demonstrated that the microenvironment is critical for ER+ tumor cells; by grafting them into milk ducts >90% take rates are achieved and many features of the human disease are recapitulated. This intra-ductal (ID) approach holds promise for personalized medicine, yet human and murine stroma are organized differently and this and other species specificities may limit the value of this model. Here, we analyzed 21 ER+ ID-PDXs histopathologically. We find that ID-PDXs vary in extent and define four histopathological patterns: flat, lobular,in situ, and invasive, which occur in pure and combined forms. The ID-PDXs replicate earlier stages of tumor development than their clinical counterparts. Micrometastases are already detected when lesions appearin situ. Tumor extent, histopathological patterns, and metastatic load correlate with biological properties of their tumors of origin. Our findings add evidence to the validity of the intraductal model forin vivostudies of ER+ breast cancer and raise the intriguing possibility that tumor cell dissemination may occur earlier than currently thought.Conflict of interest statement:The authors declare no conflict of interest.

scholarly journals Liposomal trichostatin A: therapeutic potential in hormone-dependent and -independent breast cancer xenograft models

2011 ◽  
Vol 6 (2) ◽  
Author(s):  
Giorgia Urbinati ◽  
Véronique Marsaud ◽  
Valérie Nicolas ◽  
Juliette Vergnaud-Gauduchon ◽  
Jack-Michel Renoir
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Trichostatin A ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Fluorescence Confocal Microscopy ◽  
D Cells ◽  
Tumor Accumulation

Abstract: Trichostatin A (TSA) is one of the most potent histone deacetylase inhibitors (HDACi) in vitro but it lacks biological activity in vivo when injected intravenously owing to its fast metabolism.: TSA was incorporated into Stealth: In estrogen receptor α (ERα)-positive MCF-7 and T47-D cells, TSA induced a long-term degradation of cyclin A and a proteasome-dependent loss of ERα and cyclin D1, allowed derepression of p21: Such anticancer activity of TSA-lipo is exp-lained by the protection provided by HDACi encapsulation and by the strong tumor accumulation of the nanocarriers as revealed by fluorescence confocal microscopy experi-ments. Together with its lack of toxicity, the enhanced stability of TSA-lipo in vivo justifies its development for therapeutic use in the treatment estradiol-dependent and -independent breast cancers.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

Multiple forms of estrogen receptor-α in cerebral blood vessels: regulation by estrogen

2003 ◽  
Vol 284 (1) ◽  
pp. E184-E192 ◽  
Author(s):  
Chris Stirone ◽  
Sue P. Duckles ◽  
Diana N. Krause
Keyword(s):  
Estrogen Receptor ◽  
Blood Vessels ◽  
Estrogen Receptor Α ◽  
26S Proteasome ◽  
Target Tissue ◽  
Female Rat ◽  
Cerebral Vasculature ◽  
Cerebral Blood Vessels ◽  
Multiple Forms

The cerebral vasculature is an important target tissue for estrogen, as evidenced by significant effects of estrogen on vascular reactivity and protein levels of endothelial nitric oxide synthase and prostacyclin synthase. However, the presence, localization, and regulation of estrogen receptors in the cerebral vasculature have not been investigated. In this study, we identified the presence of estrogen receptor-α (ER-α) in female rat cerebral blood vessels and localized this receptor to both smooth muscle and endothelial cells by use of immunohistochemistry and confocal microscopy. With immunoblot analysis, multiple forms of ER-α were detected at 110, 93, 82, 50, and 45 kDa in addition to a relatively weak band corresponding to the 66-kDa putative unmodified receptor. The 82-kDa band was identified as Ser118-phosphorylated ER-α, whereas the 50-kDa band lacks the normal NH2 terminus, suggestive of an ER-α splice variant. Lower molecular mass bands persisted after in vivo inhibition of 26S proteasome activity with lactacystin, whereas the 110- and 93-kDa bands increased. All forms of ER-α in cerebral vessels were decreased after ovariectomy but significantly increased after chronic estrogen exposure in vivo.

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 Loss of an Estrogen Receptor Isoform (ERαΔ3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

1997 ◽  
Vol 11 (13) ◽  
pp. 2004-2015 ◽  
Author(s):  
I. Erenburg ◽  
B. Schachter ◽  
R. Mira y Lopez ◽  
L. Ossowski
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Vector Control ◽  
Cancer Cells ◽  
Dominant Negative ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Normal Breast Epithelium ◽  
Anchorage Independent Growth

Abstract Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ERα) isoform, missing exon 3 (ERαΔ3), to the full-length ERα, in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduction of this ratio in cancer cells (P &lt; 0.0001). To test what functions may have been affected by the loss of ERαΔ3, stable clones of MCF-7 cells expressing ectopic ERαΔ3 protein, at the range of physiological ERα, were generated. In vector-transfected controls the ERαΔ3-mRNA and protein were less than 10% while in the ERαΔ3-expressing clones, ERαΔ3-mRNA and protein ranged from 36–76% of the total ERα. Estrogen (E2) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ERαΔ3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ERαΔ3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ERαΔ3-expressing clones was reduced by 50–68%, while their exponential growth rate was only slightly (14.5 ± 5%) lower. The in vivo invasiveness of the ERαΔ3-expressing cells was significantly reduced (P = 0.007) by up to 79%. E2 stimulated anchorage-independent growth of the pMV7 vector control cells, but reduced it to below baseline levels in ERαΔ3 clones. The reduction of the pS2 response to E2 in the ERαΔ3-expressing clones and the E2 block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ERαΔ3. These observations suggest that E2 may activate an additional ERαΔ3-dependent inhibitory pathway. The drastic reduction of ERαΔ3 to ERα ratio in breast cancer, and the fact that when present in breast cancer cells this isoform leads to a suppression, rather than enhancement, of the transformed phenotype by E2 suggests that the regulation of ERα-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer

2019 ◽  
Vol 11 (2) ◽  
pp. 118-128 ◽  
Author(s):  
Rajagopal Kalirajan ◽  
Arumugasamy Pandiselvi ◽  
Byran Gowramma ◽  
Pandiyan Balachandran
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
In Silico ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Breast Cancers ◽  
Molecular Docking Study ◽  
In Silico Admet

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

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