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Estrogen-related receptor alpha (ERRα) promotes the migration, invasion and angiogenesis of breast cancer stem cell-like cells

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Abstract

Breast cancer progression, metastasis and recurrence are largely driven by breast cancer stem cells (BCSCs), which constitute a subset of tumor cells exhibiting stem cell characteristics. In this study, we evaluated the role of estrogen-related receptor alpha (ERRα) in the migration, invasion and angiogenesis of BCSCs. The inhibition of ERRα using XCT790 or knockdown of ERRα using shRNA inhibited the mammosphere formation efficiency, as well as the migration and invasion of BCSCs derived from the mammospheres of MCF7 and MDA-MB-231 (MB231) cells. Conversely, the overexpression of ERRα significantly increased the migration and invasion of BCSCs derived from the mammosphere. In addition, the XCT790 treatment or shERRα significantly downregulated the epithelial-mesenchymal transition (EMT), as evidenced by the downregulation in the expression of vimentin, Snail, Slug and N-cadherin in the mammospheres of MCF7 and MB231 cells. The chorioallantoic membrane assay showed that the conditioned media from XCT790-treated and shERRα cells significantly inhibited blood vessel formation and vessel length. Furthermore, XCT790 treatment or shERRα also downregulated the expression of molecular markers of angiogenesis, such as VEGF-A and Ang-2 in the mammospheres. Conversely, the overexpression of ERRα in MCF7 cells significantly increased both EMT and angiogenesis. These findings suggest that ERRα inhibits the migration, invasion and angiogenesis of BCSCs, suggesting as a potential target for breast cancer therapy.

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Data availability

Data is provided within the manuscript or supplementary information files. Any other data available from the corresponding author upon reasonable request.

Abbreviations

Ang-2:

Angiotensin-2

BCSC:

Breast cancer stem cell

bFGF:

Basic fibroblast growth factor

CSC:

Cancer stem cell

DMEM:

Dulbecco’s modified eagle medium

EGF:

Epidermal growth factor

ER:

Estrogen receptor

ERRα:

Estrogen-related receptor alpha

EMT:

Epithelial-mesenchymal transition

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

HER2:

Human epidermal growth factor receptor 2

L15:

Leibovitz 15

MB231:

MDA-MB-231

MFE:

Mammosphere forming efficiency

TNBC:

Triple-negative breast cancer

VEGF:

Vascular endothelial growth factor

XCT790:

3-[4-(2,4-Bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl) acrylamide

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Acknowledgements

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Funding

This work was supported by the Indian Council of Medical Research (ICMR) (45/30/2020-BIO/BMS), Government of India and Science and Engineering Research Board (SERB), DST (EMR/2016/006964). KM, MP and JP are supported by Research Fellowships from UGC, ICMR and CSIR, respectively, Government of India. We also acknowledge the infrastructure support available through the DBT-BUILDER program (BT/INF/22/SP42155/2021).

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Authors and Affiliations

  1. School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, Odisha, 751024, India

    Kartik Muduli, Jagannath Pradhan, Monica Prusty, Archana Priyadarshini Samal, K Sony Reddy & Selvakumar Elangovan

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  1. Kartik Muduli
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Contributions

Conceptualization, KM, SE and KSR; methodology, KM, JP, MP, APS and SE; validation, KM, JP, APS and SE; analysis, KM, JP and SE; writing-original draft preparation, KM and SE; writing-review and editing, KM, JP, MP, KSR and SE; supervision, KSR and SE; project administration, SE; funding acquisition, KM and SE. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Selvakumar Elangovan.

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Muduli, K., Pradhan, J., Prusty, M. et al. Estrogen-related receptor alpha (ERRα) promotes the migration, invasion and angiogenesis of breast cancer stem cell-like cells. Med Oncol 41, 78 (2024). https://doi.org/10.1007/s12032-024-02329-1

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