ZNF703 promotes Triple-Negative breast cancer cell progression and in combination with STK11 predicts disease recurrence (ZS -TNBC Model).

Abstract

Background: It is largely unidentified concerning the underlying genetic causes responsible for triple-negative breast cancers (TNBC), with unpredictable disease recurrence. This study aimed to examine the role of ZNF703 (Zinc finger 703) in the malignant behaviors of TNBC and its role in predicting disease-free survival (DFS).

Methods: After downregulation of ZNF703 with short interfering RNA (siRNA), we examined the proliferation of TNBC cell line MDA-MB-231 by sulforhodamine B (SRB) assay, the invasion of cells by a transwell invasion model, and the migration of cells by the monolayer wound-healing experiment. mRNA-sequencing data of ZNF703, BRCA1, BRCA2, PALB2, CHEK2, CDH1, PTEN, STK11, ATM, and TP53, and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset for a total of 157 stage I-III TNBC samples. The selection of modeling features was executed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm to avoid model overfitting. The TIMER 2.0 algorithm determined the associations between immune score and gene expressions. Kaplan-Meier analysis was conducted to plot survival analyses.

Results: The aggressive tumor morphology, cell proliferation, cell migration, and cell invasion were partly reversed by the siRNA knockdown of ZNF703 in MDA-MB-231 cells. ZNF703 knockdown markedly enhanced the killing ability of cisplatin These phenomena were verified by another TNBC cell line BT-549. Patients with high expression of ZNF703 had an inferior DFS for TNBC patients at 8 years [Hazard ratio (HR) for high expression vs. low expression was 2.71; 95 %CI, 1.03 to 7.14, P = 0.044]. Receiver Operating Characteristic (ROC) curve was also developed, indicating the area under the curve (AUC) was 0.744 (95 %CI, 0.628 to 0.861) at 5 years and 0.738 (95 %CI, 0.552 to 0.924) at 8 years, respectively. In addition, LASSO regression results showed that the optimal penalization parameter corresponds to two prognostic genes - ZNF703 and STK11. The risk score was computed as Risk Score (RS) = 0.1033*ZNF703 + 0.2131*STK11 (named "ZS -TNBC model"). The high expression of both ZNF703 and STK11 had as high as 7.035 HR in comparison to the low-expression category (95 %CI, 2.044 to 24.206, P = 0.00197).

Conclusion: ZNF703 is required for the growth, invasion, and migratory behavior of TNBC cells. Downregulation of ZNF703 increases cisplatin efficacy. This study suggests that either ZNF703 alone or in conjunction with STK11 can be utilized to predict DFS in TNBC.