MiR-4521 perturbs FOXM1-mediated DNA damage response in breast cancer

Front Mol Biosci. 2023 Mar 21:10:1131433. doi: 10.3389/fmolb.2023.1131433. eCollection 2023.

Abstract

Introduction: Forkhead (FOX) transcription factors are involved in cell cycle control, cellular differentiation, maintenance of tissues, and aging. Mutation or aberrant expression of FOX proteins is associated with developmental disorders and cancers. FOXM1, an oncogenic transcription factor, is a promoter of cell proliferation and accelerated development of breast adenocarcinomas, squamous carcinoma of the head, neck, and cervix, and nasopharyngeal carcinoma. High FOXM1 expression is correlated with chemoresistance in patients treated with doxorubicin and Epirubicin by enhancing the DNA repair in breast cancer cells. Method: miRNA-seq identified downregulation of miR-4521 in breast cancer cell lines. Stable miR-4521 overexpressing breast cancer cell lines (MCF-7, MDA-MB-468) were developed to identify miR-4521 target gene and function in breast cancer. Results: Here, we showed that FOXM1 is a direct target of miR-4521 in breast cancer. Overexpression of miR-4521 significantly downregulated FOXM1 expression in breast cancer cells. FOXM1 regulates cell cycle progression and DNA damage response in breast cancer. We showed that miR-4521 expression leads to increased ROS levels and DNA damage in breast cancer cells. FOXM1 plays a critical role in ROS scavenging and promotes stemness which contributes to drug resistance in breast cancer. We observed that breast cancer cells stably expressing miR-4521 lead to cell cycle arrest, impaired FOXM1 mediated DNA damage response leading to increased cell death in breast cancer cells. Additionally, miR-4521-mediated FOXM1 downregulation perturbs cell proliferation, invasion, cell cycle progression, and epithelial-to-mesenchymal progression (EMT) in breast cancer. Discussion: High FOXM1 expression has been associated with radio and chemoresistance contributing to poor patient survival in multiple cancers, including breast cancer. Our study showed that FOXM1 mediated DNA damage response could be targeted using miR-4521 mimics as a novel therapeutic for breast cancer.

Keywords: DNA damage; FoxM1; breast cancer; cell cycle; miR-4521.

Grants and funding

This work was supported by Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India (YSS/2015/001051, and CRG/2020/004681). RK was supported by Indian Council of Medical Research-Senior Research Fellowship (File No: 2019-0278/GEN-BMS), Government of India. The infrastructure support and funding from DST-FIST, Government of India, TIFAC-CORE, DBT-BUILDER grant, Government of India, VGST Karnataka, K-FIST and Manipal Academy of Higher Education is gratefully acknowledged.