scholarly journals Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 543
Author(s):  
Rosaria Benedetti ◽  
Chiara Papulino ◽  
Giulia Sgueglia ◽  
Ugo Chianese ◽  
Tommaso De Marchi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Mirna Expression ◽  
Estrogen Receptor Alpha ◽  
Estrogen Signaling ◽  
Integrated Analysis ◽  
Tumor Resistance ◽  
Estrogen Receptor Signaling

The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.

scholarly journals Obesity-Altered Adipose Stem Cells Promote ER+ Breast Cancer Metastasis through Estrogen Independent Pathways

2019 ◽  
Vol 20 (6) ◽  
pp. 1419 ◽  
Author(s):  
Rachel A. Sabol ◽  
Adam Beighley ◽  
Paulina Giacomelli ◽  
Rachel M. Wise ◽  
Mark A. A. Harrison ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Estrogen Receptor ◽  
Tumor Growth ◽  
Estrogen Receptor Alpha ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Adipose Stem Cells ◽  
Estrogen Signaling ◽  
Promote Tumor Growth

Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER+) breast cancer (BC) tumor growth and metastasis. In this study, we evaluate the effect of obASCs on ER+BC outside of the ERα signaling axis using breast cancer models with constitutively active ERα resulting from clinically relevant mutations (Y537S and D538G). We found that while obASCs promote tumor growth and proliferation, it occurs mostly through abrogated estrogen signaling when BC has constitutive ER activity. However, obASCs have a similar promotion of metastasis irrespective of ER status, demonstrating that obASC promotion of metastasis may not be completely estrogen dependent. We found that obASCs upregulate two genes in both ER wild type (WT) and ER mutant (MUT) BC: SERPINE1 and ABCB1. This study demonstrates that obASCs promote metastasis in ER WT and MUT xenografts and an ER MUT patient derived xenograft (PDX) model. However, obASCs promote tumor growth only in ER WT xenografts.

The Evolving Role of the Estrogen Receptor Mutations in Endocrine Therapy-Resistant Breast Cancer

2017 ◽  
Vol 19 (5) ◽  
Author(s):  
Rinath Jeselsohn ◽  
Carmine De Angelis ◽  
Myles Brown ◽  
Rachel Schiff
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy

scholarly journals miR-489 confines uncontrolled estrogen signaling through a negative feedback mechanism and regulates tamoxifen resistance in breast cancer

2020 ◽  
Author(s):  
Mithil Soni ◽  
Ozge Saatci ◽  
Yogin Patel ◽  
Manikanda Raja Keerthi Raja ◽  
Xinfeng Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Lines ◽  
Tamoxifen Resistance ◽  
Resistant Cell ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Tamoxifen Resistant ◽  
Hormonal Therapies

Abstract Background Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor (ER) positive tumors and are associated with better prognosis due to their response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. In the current study, we aimed to evaluate miR-489 as a novel molecular target to combat tamoxifen resistance.Methods Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen resistant cell lines unveiled the potential role of miR-489 in regulation of estrogen signaling and development of tamoxifen resistance. We manipulated miR-489 expression in breast cancer cell lines by transient transfection of miR-489 mimic or establishment of knockout cell lines using the CRISPR/Cas9 system to study the reciprocal regulation of miR-489 and estrogen/ER signaling pathways. Cell proliferation, tumor sphere formation assay and flow cytometry analysis were conducted to investigate the role of miR-489 on estrogen-induced cell proliferation, cancer stem cells expansion and development of tamoxifen resistance.Results miR-489 expression was significantly downregulated in tamoxifen-resistant cell lines. Low levels of miR-489 were associated with poor clinical outcomes in patients with hormone treatment. In vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen regulated miRNA that negatively regulated estrogen receptor signaling by using at least the following two mechanisms: i) modulation of ER phosphorylation status by inhibiting MAPK and AKT kinase activities; ii) regulation of nucleus to cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 could break the positive feed-forward loop between estrogen-ERα axis and p38 MAPK in breast cancer cells which was necessary for its function as transcription factor.Conclusion Our study unveiled the underlying molecular mechanism by which miR-489 regulates estrogen signaling pathway through a negative feedback loop and uncovered its role in the development of and overcoming tamoxifen resistance in breast cancers.

Sign in / Sign up

Export Citation Format

Share Document