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Estrogen-Related Receptor Alpha (ERRα) Promotes Cancer Stem Cell-Like Characteristics in Breast Cancer

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Abstract

Cancer stem cells drive tumor initiation, invasion, metastasis and recurrence. In the present study, we have evaluated the role of ERRα in the maintenance of breast cancer stem cells (BCSCs) using breast cancer cell lines. The inhibition of ERRα with the inverse agonist, XCT-790, or the knockdown of ERRα in breast cancer cells significantly reduced the mammosphere formation efficiency and mammosphere size along with a significant reduction in the CD44+/CD24− BCSCs. Treatment with XCT-790 significantly downregulated expression of the transcription factors involved in stem cell maintenance such as Oct4, Klf4, Sox2, Nanog and c-Myc in the mammosphere forming stem cells of MCF7 and MDA-MB-231. In addition, XCT-790 induced cell cycle arrest and apoptosis in the mammosphere-forming cells. The knockdown or inhibition of ERRα downregulated the expression of Notch1 and β-catenin, whereas the overexpression of ERRα in MCF7 cells upregulated the expression of these proteins. Moreover, the inhibition of ERRα synergistically enhanced the efficacy of paclitaxel in inhibiting the BCSCs. These results show that ERRα is crucial for the maintenance of BCSCs and suggest that ERRα could be a potential target for breast cancer treatment.

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Data Availability

The data generated in this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Abbreviations

ALDH:

Aldehyde dehydrogenase

BCSC:

Breast cancer stem cell

bFGF:

Human basic fibroblast growth factor

c-Myc:

Cellular myelocytomatosis oncogene

CSC:

Cancer stem cell

DMEM:

Dulbecco’s modified eagle medium

EGF:

Recombinant human epidermal growth factor

ER:

Estrogen receptor

ERRα:

Estrogen-related receptor alpha

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

HER2:

Human epidermal growth factor receptor 2

KLF4:

Kruppel-like factor 4

L15:

Leibovitz 15

M231:

MDA-MB-231

M468:

MDA-MB-468

NFkβ:

Nuclear factor kappa B

OCT4:

Octamer-binding transcription factor 4

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha

PI:

Propidium Iodide

PR:

Progesterone receptor

SOX2:

SRY (sex determining region Y)-box 2

TGFβ:

Transforming growth factor beta

TNBC:

Triple-negative breast cancer

VEGF:

Vascular endothelial growth factor

XCT-790:

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

The graphical abstract has been created using BioRender.

Funding

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

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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, Monica Prusty, Jagannath Pradhan, Archana Priyadarshini Samal, Bikash Sahu, Debanjan Singha Roy, K. Sony Reddy & Selvakumar Elangovan

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  1. Kartik Muduli
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Contributions

KM, KSR and SE contributed to the study conception and design. KM, MP, JP, APS and DSR performed the experiments, data collection and analysis. BS analyzed the flow cytometry data. SE contributed to the project administration, supervision and funding acquisition. KM, SR, and SE prepared the first draft of the manuscript and all authors contributed to the revisions. All authors read and approved the final manuscript.

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Correspondence to Selvakumar Elangovan.

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Muduli, K., Prusty, M., Pradhan, J. et al. Estrogen-Related Receptor Alpha (ERRα) Promotes Cancer Stem Cell-Like Characteristics in Breast Cancer. Stem Cell Rev and Rep 19, 2807–2819 (2023). https://doi.org/10.1007/s12015-023-10605-2

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