The antiviral drug telaprevir induces cell death by reducing <scp><i>FOXA1</i></scp> expression in estrogen receptor α (<scp>ERα</scp>)‐positive breast cancer cells

Bartoloni, Stefania; Leone, Stefano; Pescatori, Sara; Cipolletti, Manuela; Acconcia, Filippo

doi:10.1002/1878-0261.13303

Cited by 6 publications

(9 citation statements)

References 62 publications

(96 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, we demonstrated that the antiviral drug telaprevir (Tel) induces degradation of the ERα and hampers the proliferation of several ERα-positive BC cell lines 23,24 . Given the sensitivity of ERα-positive BC cell lines to various kinase inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We also used a hypothesis-driven approach to identify additional kinases involved in regulating receptor intracellular levels by conducting Affymetrix analyses on ERα-positive BC cells treated with telaprevir (Tel), an antiviral drug inducing ERα degradation by inhibiting the kinases IGF1-R and AKT 23,24 . Surprisingly, we found that Tel reduced the mRNA levels of many kinases, most of which belonged to the kinase signature that distinguishes LumA BC from basal BC 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Given the sensitivity of ERα-positive BC cell lines to various kinase inhibitors (Fig. 1), and the fact that we previously discovered that Tel inhibits the IGF1-R and AKT kinases in BC cells by reducing their intracellular levels and phosphorylation status 24 , we proceeded to conduct Affymetrix analysis on Tel-treated ERα-positive BC cell lines to explore if additional kinases might be influenced by this drug and potentially involved in the regulation of receptor stability. For this purpose, we decided to undertake an unbiased approach by employing three different cell lines modelling the three major subtypes of ERα-positive breast tumors: MCF-7 cells were chosen because they represent the LumA phenotype, while BT-474 cells were selected because they belong the LumB class of BC.…”

Section: Identification Of Melk As a Kinase Regulating Erα Stabilitymentioning

confidence: 99%

See 2 more Smart Citations

Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer

Bartoloni,

Pescatori,

Bianchi

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Breast cancer (BC) is a leading cause of global cancer-related mortality in women, necessitating accurate tumor classification for timely intervention. Molecular and histological factors, including PAM50 classification, estrogen receptor α (ERα), breast cancer type 1 susceptibility protein (BRCA1), progesterone receptor (PR), and HER2 expression, contribute to intricate BC subtyping. Through in silico screenings and multiple BC cell line investigations, we identified enhanced sensitivity of ERα-positive BC cell lines to ALK and MELK inhibitors, inducing ERα degradation and diminishing proliferation in specific BC subtypes. MELK inhibition attenuated ERα transcriptional activity, impeding E2-induced gene expression, and hampering proliferation in MCF-7 cells. Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors’ potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Melk As a Kinase Regulating Erα Stabilitymentioning

confidence: 99%

See 1 more Smart Citation

Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer

Bartoloni,

Pescatori,

Bianchi

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Wykazano, że telaprevir zmniejsza wewnątrzkomórkowe poziomy ERα, dereguluje sygnalizację E2:ERα i hamuje proliferację indukowaną przez E2 w komórkach raka piersi [23]. Sugeruje to potencjalne wykorzystanie telapreviru w leczeniu pierwotnego i przerzutowego raka piersi [24], lecz warto jednak przeprowadzić więcej badań klinicznych, które mogłyby ocenić ewentualne działania niepożądane tego leku przed rozpoczęciem badań klinicznych z udziałem ludzi.…”

Section: Rak Piersiunclassified

DAA - directly acting antivirals - as a new, more efficient solution of the chronic hepatitis C treatment and theirs various application.

ABRAM¹,

Patryk

ADAMUS³

et al. 2023

J Educ Health Sport

View full text Add to dashboard Cite

Introduction Cirrhosis is a condition in which the liver becomes fibrotic following damage to the liver and transforms the architecture of the organ into regenerative nodules. The disease is caused 30% by HCV infection, resulting in a risk of severe complications and death. Since the use of direct-acting antivirals ( DAAs) for the treatment of chronic HCV, sustained virological response (SVR) rates have begun to increase, even in treatment-resistant cases. Studies have also shown that DAAs may have applications in other viral diseases and even In the treatment of breast cancer. Aim of the study The purpouse of our study was to review scientific articles to show the efficiency and potential use of DAAs in the treatment of chronic HCV, and to identify possible directions for further research. Methods and materials We reviewed the English literature in the PubMed, using the key words: "simeprevir" ; "sofosbuvir" ; "velpatasvir" ; "telaprevir" ; "chronic hepatitis C". Results Studies have shown that the therapeutic regimens currently being designed with (DAAs) offer the possibility of treating almost the entire population with hepatitis C, while reducing side effects of interferon therapy such as increased AST, ALT activities, diarrhoea, vomiting, nausea and depression. They remain effective and tolerable, regardless of the stage of cirrhosis and associated serious co-morbidities. Analysis of studiem shows, that DAAs also show efficacy against other disease such as breast cancer, MRSA infections, SARS-CoV-2 or flavivirus infection. Conclusion All (DAAs) are effective in the treatment of patients with HCV, including cirrhosis. They result in significant improvements in prognosis and clinical outcomes. Promising results have been obtained in published data on the effect of DAAs against disease entities other than HCV, suggesting the rationale for future clinical trials to further the hypothesis of the increased potential of these drugs.

show abstract

“…Furthermore, we have previously reported a selection of Food and Drug Administration (FDA)-approved drugs that do not directly bind to the ERα but have the ability to induce its degradation by activating various cellular pathways [5][6][7][8]. These drugs have also demonstrated the capability to inhibit the proliferation of cells expressing the Y537S ERα variant [5][6][7][8]. This indicates that promoting the degradation of ERα is su cient to hinder cell proliferation, regardless of the drug's ability to directly bind to the receptor [3].…”

Section: Introductionmentioning

confidence: 99%

PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells

Cipolletti

Acconcia

2023

Preprint

Self Cite

View full text Add to dashboard Cite

Purpose: Metabolic reprogramming in breast cancer (BC) subtypes offers potential personalized treatment targets. Estrogen receptor α (ERα)-positive BC patients undergoing endocrine therapy (ET) can develop ET-resistant metastatic disease. Specific mutations, like Y537S in ERα, drive uncontrolled metastatic cell proliferation. Targeting mutant receptor levels shows promise for inhibiting growth in metastatic BC expressing ERα variants. Additionally, metabolic reprogramming occurs in ERα Y537S mutant cells. Consequently, we conducted a screen to identify metabolic proteins reducing intracellular levels of ERα Y537S and inhibiting cell proliferation. Methods: Nine metabolic proteins were identified in a siRNA-based screen, with phosphomannose mutase 2 (PMM2) showing the most promise. We measured the impact of PMM2 depletion on ERα stability and cell proliferation in ERα Y537S mutant cells. Additionally, we tested the effect of PMM2 reduction on the hyperactive phenotype of the mutant and its proliferation when combined with metastatic BC treatment drugs. Results: PMM2 emerged as a significant target due to its correlation with better relapse-free survival, overexpression in ERα-positive tumors, and its elevation in ERα Y537S-expressing cells. Depletion of PMM2 induces degradation of ERα Y537S, inhibits cell proliferation, and reduces ERα signaling. Notably, reducing PMM2 levels re-sensitizes ERα Y537S-expressing cells to certain ET drugs and CDK4/CDK6 inhibitors. Mechanistically, depletion of PMM2 leads to a reduction in ESR1 mRNA levels, resulting in decreased ERα receptor protein expression. Furthermore, reduction of PMM2 decreases FOXA1 levels, which plays a crucial role in ERα regulation. Conclusions: Our findings establish PMM2 as an innovative therapeutic target for metastatic BC expressing the ERα Y537S variant, offering alternative strategies for managing and treating this disease.

show abstract

The antiviral drug telaprevir induces cell death by reducing FOXA1 expression in estrogen receptor α (ERα)‐positive breast cancer cells

Cited by 6 publications

References 62 publications

Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer

Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer

DAA - directly acting antivirals - as a new, more efficient solution of the chronic hepatitis C treatment and theirs various application.

PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells

Contact Info

Product

Resources

About