Transcription factor E2F8 is a therapeutic target in the basal-like subtype of breast cancer

Jing Zheng; Jingyi Huang; Jinquan Xia; Wenbin Zhou; Lingyun Dai; Sihang Lin; Lin Gao; Chang Zou

doi:10.3389/fonc.2023.1038787

Transcription factor E2F8 is a therapeutic target in the basal-like subtype of breast cancer

Front Oncol. 2023 Feb 6:13:1038787. doi: 10.3389/fonc.2023.1038787. eCollection 2023.

Authors

Jing Zheng¹, Jingyi Huang², Jinquan Xia³, Wenbin Zhou⁴, Lingyun Dai³, Sihang Lin⁴, Lin Gao³, Chang Zou^{3

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Affiliations

¹ Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
² Department of Clinical Medical Research Center, The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
³ Department of Clinical Medical Research Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁴ Department of Thyroid and Breast Surgery, Department of General Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁵ Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, Guangdong, China.
⁶ School of Life and Health Sciences, The Chinese University of Kong Hong, Shenzhen, Guangdong, China.

Abstract

Introduction: Tumorigenesis in breast cancers usually accompanied by the dysregulation of transcription factors (TFs). Abnormal amplification of TFs leads aberrant expression of its downstream target genes. However, breast cancers are heterogeneous disease with different subtypes that have distinguished clinical behaviours, and the identification of prognostic TFs may enable to provide diagnosis and treatment of breast cancer based on subtypes, especially in Basal-like breast cancer.

Methods: The RNA-sequencing was performed to screen differential TFs in breast cancer subtypes. The GEPIA dataset analysis was used to analyze the genes expression in invasive breast carcinoma. The expression of MYBL2, HOXC13, and E2F8 was verified by qRT-PCR assay in breast cancers. The depiction analysis of co-expressed proteins was revealed using the STRING datasets. The cellular infiltration level analysis by the TISIDB and TIMER databases. The transwell assay was performed to analyze cellular migration and invasion. CCK-8 assay was used to evaluate cellular drug susceptibility for docetaxel treatment. Predicted targeted drugs in breast cancers by GSCA Lite database online.

Results: Kaplan-Meier plotter suggested that high expression of both E2F8 and MYBL2 in Basal-like subtype had a poor relapse-free survival. Functional enrichment results identified that apoptosis, cell cycle, and hormone ER pathway were represented the crucial regulation pathways by both E2F8 and MYBL2. In the meantime, database analysis indicated that high expression of E2F8 responded to chemotherapy, while those patients of high expression of MYBL2 responded to endocrinotherapy, and a positive correlation between the expression of E2F8 and PD-L1/CTLA4. Our cell line experiments confirmed the importance of E2F8 and MYBL2 in proliferation and chemotherapy sensitivity, possibly, the relationship with PD-L1. Additionally, we also observed that the up-regulation of E2F8 was accompanied with higher enrichments of CD4+ T cells and CD8+ T cells in breast cancers.

Conclusion: Taken together, our findings elucidated a prospective target in Basal-like breast cancer, providing underlying molecular biomarkers for the development of breast cancer treatment.

Keywords: E2F8; biomarker; breast cancer; immune checkpoint molecules; transcription factors.

Grants and funding

This work was supported by grants from the Science and Technology Foundation of Shenzhen City (grant numbers JCYJ20190806154610953 to LG), the National Natural Science Foundation of China (grant numbers 82273041 to LG, 82002929 to LG, 32070748 to LD), the Basic and Applied Basic Research Foundation of Guangdong Province (grant numbers 2020A1515111072 to LG, 2020B1515120032 to CZ), and the Shenzhen Key Medical Discipline Construction Fund (grant number SZXK053).