ID4 Promotes Breast Cancer Chemotherapy Resistance via CBF1-MRP1 Pathway

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.

Notch signaling in female cancers: a multifaceted node to overcome drug resistance

“…The authors clearly demonstrated that N1ICD induces the transcription of MRP1/ABCC1 by interacting with CBF1 and its effects in promoting drug resistance by the induction of this transporter [ 201 ] . Consistent with these findings, in a recent study, Zhang et al [ 202 ] demonstrated that the inhibitor of DNA-binding 4 (ID-4) protein sustains chemo-resistance in BC because it is positively associated with Notch1 pathway by favoring CBF1-MRP1/ABCC1. Moreover, Kim et al [ 203 ] documented that Notch1 and MRP1/ABCC1 are upregulated after chemotherapy and their protein expression is positively correlated in BC clinical samples.…”

“…Furthermore, ectopic expression of the intracellular domain of Notch1 (N1ICD) correlated to the increase of another ABC transporter (MRP1/ABCC1), both at mRNA and protein levels, in BC cell lines. The authors clearly demonstrated that N1ICD induces the transcription of MRP1/ABCC1 by interacting with CBF1 and its effects in promoting drug resistance by the induction of this transporter [201] . Consistent with [193] *Notch receptor or ligand involved, when specified.…”

The prognostic and clinical significance of IFI44L aberrant downregulation in patients with oral squamous cell carcinoma

“…HOXB2 serves as a tumor promotor in bladder cancer [ 54 ], colorectal cancer [ 55 ], and pancreatic cancer [ 56 ]. The oncogenic role of ID4 has also been reported in lung cancer [ 57 ], hepatocellular carcinoma [ 58 ], and breast cancer [ 59 ]. IFI44L serves as a tumor suppressor in hepatocellular carcinoma; in hepatocellular carcinoma patients, low IFI44L expression is associated with tumor size, recurrence, advanced stage and poor clinical survival [ 60 ].…”

Overexpression of EWSR1 (Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1) predicts poor survival in patients with hepatocellular carcinoma

“…Antigen retrieval was performed by incubating the slides with 0.01 M citrate buffer (pH 6.0) at 100°C for 10 min. Standard immunohistochemical protocol was then implemented using a Ventana Benchmark XT autostainer (Ventana Medical Systems, Tucson, AZ, USA) as described previously [ 13 ]. Negative control slides omitting the primary antibodies were used for all assays.…”