scholarly journals Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3840
Author(s):  
Claudia Busonero ◽  
Stefano Leone ◽  
Fabrizio Bianchi ◽  
Elena Maspero ◽  
Marco Fiocchetti ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Estrogen Receptor Α ◽  
New Drugs ◽  
Gene Profiling ◽  
Breast Cancers ◽  
Expression Of Genes ◽  
Approved Drugs ◽  
In Cells

Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

scholarly journals Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianing Ding ◽  
Peng Kuang
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Estrogen Receptor Α ◽  
Good Prognosis ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Post Translational Modification ◽  
Positive Breast Cancer

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.

scholarly journals A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

2021 ◽  
Vol 22 (6) ◽  
pp. 2915
Author(s):  
Manuela Cipolletti ◽  
Stefania Bartoloni ◽  
Claudia Busonero ◽  
Martina Parente ◽  
Stefano Leone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bioactive Compounds ◽  
Estrogenic Activity ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Cellular Models ◽  
Cancer Models ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
Anti Fungal

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

Endocrine therapy-based strategies with different endocrine sensitivity statuses for hormone receptor positive/HER2 negative metastatic breast cancer: A network meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1062-1062
Author(s):  
Jiani Wang ◽  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Optimal Treatment ◽  
Hormone Receptor Positive ◽  
Direct Head

1062 Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Since the absence of direct head-to-head comparisons for all regimens, decision-making guidelines are urgently needed for different endocrine sensitivity statuses. This study is to evaluate the efficacy of ET-based regimens in patients with HR+/HER2- MBC and to assess the heterogeneity among different compounds with a particular focus on their ability to improve survival outcomes. Methods: This network meta-analysis of phase II/III randomized controlled trials (RCTs) with at least one ET in HR+/HER2- MBC were enrolled. Based on the endocrine responses, participants were stratified into endocrine therapy sensitivity (ETS) and endocrine therapy resistance (ETR) groups. Primary endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed by bayesian algorithms and primarily measured as surface under the cumulative ranking curve (SUCRA). Results: A total of 42 trials (22917 patients) were included. Regarding PFS, cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) +fulvestrant 500mg (F500) was recommended for the ETS group (SUCRA = 76.92%), while chemotherapy was considered as the most effective option for the ETR group (SUCRA = 73.47%). For visceral metastases, CDK4/6i +aromatase inhibitors (AIs) could provide the extreme efficacy for the ETS group (SUCRA = 63.27%) while the CDK4/6i +F500 (SUCRA = 76.17%) as the prior regimen for the ETR group. For bone-only disease, CDK4/6i+F500 was preferred for both the ETS (SUCRA = 67.04%) and the ETR (SUCRA = 70.24%) group. Concerning OS, CDK4/6i+tamoxifen was estimated as the first-rank regimen for the ETS subgroup (SUCRA = 67.04%) and chemotherapy for the ETR subgroup (SUCRA = 60.02%). Regarding resistance category, abemaciclib +F500 was likely the best option with PFS, for both primary (SUCRA = 69.19%) and secondary ETR (SUCRA = 69.09%) settings, as well as primary ETR associated with OS improvement (SUCRA = 67.67%). Pictilisib +F500 could be the optimal treatment with OS for secondary ETR (SUCRA = 60.50%)group. Conclusions: The results showed that CDK4/6i + F500 was probably the most promising option in ETS, visceral ETR and bone-only disease settings in terms of PFS. OS subgroup analysis showed that different endocrine sensitivity statuses required various optimal treatment strategies.

Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer.

1987 ◽  
Vol 5 (11) ◽  
pp. 1779-1782 ◽  
Author(s):  
U Berger ◽  
J L Mansi ◽  
P Wilson ◽  
R C Coombes
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Endocrine Therapy ◽  
Tumor Cells ◽  
Epithelial Membrane Antigen ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Double Staining ◽  
Primary Tumors ◽  
Er Positive

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.

scholarly journals Еstrogen receptor α (ESR1) and SRC family kinase (LYN) gene's mutations associated with ovarian cancer endocrine therapy resistance

2021 ◽  
Vol 8 (1) ◽  
pp. 10-16
Author(s):  
E. A. Shestakova
Keyword(s):  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Therapy Resistance ◽  
Estrogen Receptor Α ◽  
Endocrine Therapy Resistance ◽  
Lyn Kinase ◽  
Esr1 Gene ◽  
Gene Coding ◽  
Pubmed Database

Recently multiple data accumulated concerning mutations in the ESR1 gene coding estrogen receptor α (mutESR1) and in the LYN gene coding non receptor tyrosine kinase SRC family member (mutLYN) that are associated with endocrine therapy resistance and that could be considered as markers of endocrine therapy efficiency. In case of gynecologic cancers including ovarian cancer the most frequent mutESR1 are ESR1L536H/P/R/V , ESR1Y537S/N/C/H, ESR1D538G that emerge in the course of hormonotherapy especially using aromatase inhibitors. mutLYN including LYNE159K, LYND189Y, LYNK209N, LYNA370T, LYNG418R, LYNA503D are also identified. mutESR1 and mutLYN increase transcriptional activity of estrogen receptor α (ERα) coded with ESR1 gene and catalytic activity of LYN kinase inducing endocrine therapy resistance. Interdependence of ESR1 and LYN genes is revealed at the level of proteins that they code as the kinases of the SRC family including LYN activate ERα-dependent transcription due to the phosphorylation of ERα at Y537 amino-acid residue that is the most frequently mutated in tumors with endocrine therapy resistance. The aim of the review is revealing the clinical correlations of mutESR1 and mutLYN with the ovarian cancer endocrine therapy resistance that opens perspectives of mutESR1 and mutLYN use as new predictive markers of ovarian cancer and development of more efficient anti-tumor medicaments. In the review the information obtained from PubMed database for the last 20 years using the following key words: ESR1, LYN, mutation(s), estrogen receptor α (ERα), LYN kinase, SRC family kinases, ovarian cancer, gynecologic(al) cancer is discussed.

scholarly journals HER2+ murine breast cancers and lung metastases differentially express a series of olfactory and vomeronasal receptors

2019 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Lung Metastases ◽  
Γδ T Cells ◽  
Metastatic Breast ◽  
Olfactory Receptors ◽  
Differentially Expressed ◽  
Breast Cancers ◽  
Expression Of Genes ◽  
Vomeronasal Receptors ◽  
Differential Transcription ◽  
Receptor Family

I previously reported that over 15% of the most differentially expressed genes in CD24+ CD73+ γδ-T cells bearing a Vγ2 chain encode olfactory receptors. Here I present evidence that differential transcription of olfactory receptors can occur in breast cancers. Global comparative analysis of the transcriptomes of metastatic breast cancer in mice revealed that a series of Olfr (olfactory) genes were differentially expressed in tumors and in metastases. Lung metastases also expressed high levels of a non-coding RNA from the vomeronasal receptor family and two vomeronasal receptors. It is unknown whether any of these olfaction molecules play important roles in initiation or maintenance of tumors and/or metastases, or whether their expression can serve to improve diagnosis and/or prognosis. Differential expression of genes of the olfactory receptor family outside of the nervous system is not restricted to hematopoietic cells, and occurs in disease as well as in development.

scholarly journals Mitochondrial Fission Regulator 2 (MTFR2) Confers anti-ER Endocrine Therapy Resistance to Breast Cancer Cells by Modulating Mitochondrial Autophagy through Direct Phosphorylation of FUNDC1

2021 ◽  
Author(s):  
Zhanqiang Zhang ◽  
Guanming Lu ◽  
Bo Lin ◽  
Yanghong Li ◽  
Fuju Li ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Breast Cancer Cells ◽  
Sequence Similarity ◽  
Mitochondrial Fission ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Endocrine Therapy Resistance ◽  
Normal Tissues ◽  
The Relationship ◽  
Proliferation And Invasion

Abstract Background: Mitochondrial fission regulator 2 (MTFR2) belongs to the MTFR1/ family with sequence similarity 54 (FAM54) family. Recently, it was reported that MTFR2 promotes the proliferation and invasion of breast cancers (BCs). However, the relationship between MTFR2 and endocrine crine therapy resistance is still unknown.Materials and methods: We collected 36 ER+ BC tissues and adjacent normal tissues and 10 samples from patients who received endocrine therapy. We detected the expression pattern of MTFR2 and the fold change in MTFR2 in cells treated with tamoxifen and letrozole. The autophagy status was also determined.Results: MTFR2 expression was upregulated in ER+ BC tissues and was strongly upregulated in the samples that were treated with endocrine therapy. Knocking out MTFR2 increased BC cell sensitivity to endocrine therapy. In addition, MTFR2 directly bound to FUNDC1 and promoted FUNDC1 phosphorylation, thus inhibiting autophagy.Conclusion: Taken together, our results indicate that increased expression of MTFR2 is associated with endocrine therapy resistance in BC cells. Our findings indicate that MTFR2 could serve as a novel therapeutic target for ER+ BC patients who suffer from endocrine therapy resistance.

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