J Cancer 2020; 11(13):3846-3857. doi:10.7150/jca.31988

Research Paper

ID4 Promotes Breast Cancer Chemotherapy Resistance via CBF1-MRP1 Pathway

Xi Zhang1,2, Guangyan Gu3, Lin Song4,5, Dan Wang6,7, Yali Xu4,5, Shuping Yang8,9, Bin Xu10, Zhixin Cao4,5, Chunmei Liu11,12, Chunming Zhao13,14, Yuanyuan Zong4,5, Yejun Qin4,5, Jiawen Xu4,5✉

1. Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
2. Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China
3. Department of Histology and Embryology, Shandong University Cheeloo College of Medicine, Jinan, 250012, Shandong, China
4. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
5. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China
6. Department of Science and education, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
7. Department of Science and education, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China
8. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
9. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China
10. Department of Pathology, Shengli Oil Field Central Hospital, Dongying, Shandong Province, 257034, P.R China
11. Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
12. Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China
13. Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, PR China
14. Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, PR China

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Citation:
Zhang X, Gu G, Song L, Wang D, Xu Y, Yang S, Xu B, Cao Z, Liu C, Zhao C, Zong Y, Qin Y, Xu J. ID4 Promotes Breast Cancer Chemotherapy Resistance via CBF1-MRP1 Pathway. J Cancer 2020; 11(13):3846-3857. doi:10.7150/jca.31988. Available from https://www.jcancer.org/v11p3846.htm

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Abstract

Chemo-resistance is considered a key problem in triple negative breast cancer (TNBC) chemotherapy and as such, an urgent need exists to identify its exact mechanisms. Inhibitor of DNA binding factor 4 (ID4) was reported to play diverse roles in different breast cancer molecular phenotypes. In addition, ID4 was associated with mammary carcinoma drug resistance however its functions and contributions remain insufficiently defined. The expression of ID4 in MCF-7, MCF-7/Adr and MDA-MB-231 breast cancer cell lines and patients' tissues were detected by RT-PCR, western blot and immunohistochemistry. Furthermore, TCGA database was applied to confirm these results. Edu and CCK8 assay were performed to detect the proliferation and drug resistance in breast cancer cell lines. Transwell and scratch migration assay were used to detected metastasis. Western blot, TCGA database, Immunoprecipitation (IP), Chromatin Immunoprecipitation (ChIP) and Luciferase reporter assay were used to investigate the tumor promotion mechanisms of ID4. In this study, we report that the expression levels of ID4 appeared to correlate with breast cancers subtype differentiation biomarkers (including ER, PR) and chemo-resistance related proteins (including MRP1, ABCG2, P-gp). Down-regulation of ID4 in MCF-7/Adr and MDA-MB-231 breast cancer cell lines significantly suppressed cell proliferation and invasion, however enhanced Adriamycin sensitivity. We further demonstrated that the oncogenic and chemo-resistant effects of ID4 could be mediated by binding to CBF1 promoter region though combination with MyoD1, and then the downstream target MRP1 could be activated. We reveal for the first time that ID4 performs its function via a CBF1-MRP1 signaling axis, and this finding provides a novel perspective to find potential therapeutic targets for breast cancer chemotherapy.

Keywords: ID4, triple negative breast cancer, chemotherapy resistance, CBF1, MRP1