A Combined Bioinformatic and Nanoparticle-Based Study Reveal the Role of ABCG2 in the Drug Resistant Breast Cancer

Abstract

Background: ATP-Binding Cassette subfamily G member 2 (ABCG2) is a semi-transport protein that plays a key role in human diseases, including bladder cancer and lung cancer, and maybe resistant to chemotherapy drugs. Objective: The present study aimed to determine the role and underlying mechanisms of breast cancer resistance protein (ABCG2) in breast cancer and to study the reversal effect of inhibiting ABCG2 expression on the drug resistance of breast cancer cells and provide new ideas for gene-targeted therapy of breast cancer. Methods: The structure and genomic alterations of ABCG2 were systematically investigated using GeneCards and cBioPortal to reveal the genetic alterations (including amplification and deep deletions) of ABCG2. We performed the correlation between ABCG2 expression and clinicopathological parameters using the data in bc-GenExMiner 4.4. Then, the protein-protein interaction and functional enrichment analysis of ABCG2 were performed based on the STRING, bc-GenExMiner 4.4, and Enrichr databases. Besides, we analyzed the pathway activity of genes that interact with ABCG2 using GSCALite and PharmGKB. Using magnetic nanoparticles polyMAG as the carrier of ABCG2-siRNA, polyMAG-ABCG2-siRNA was transfected into the Doxorubicin (DOX)-resistant breast cancer cell line MCF-7/ADR and directly into the tumors in nude mice. Patent US20150328485 points out that magnetic nanoparticles can be attached to an anti-cancer drug, such as an antibody-based anti-cancer drug. Results: We found a statistically significant correlation between ABCG2 expression and clinicopathological parameters, such as Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor-2 (HER2), and nodal status in breast cancer patients. ABCG2 is closely related to SLC2A9, KIT, ABCG1, and MRPS7, which suggests that these proteins may be functional partners of breast cancer. The expression of ABCG2 is correlated with the activation or inhibition of multiple oncogenic pathways. Moreover, we found that ABCG2 is involved in the DOX signaling pathway. The small interfering RNA (siRNA) carried by magnetic nanoparticles can reduce the expression of ABCG2, thereby significantly improving the therapeutic effect of DOX on tumors. Conclusion: Our findings provide a more in-depth understanding of ABCG2 as a biomarker for predicting DOX-resistance and insights into the development of related therapeutic targets in breast cancer.