Characterization of Potential Target Genes of Borneol in Increasing Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer: Bioinformatics and In Vitro Studies

• Published in: Asian Pacific journal of cancer prevention : APJCP Vol. 25; no. 5; pp. 1623 - 1634
• Main Authors: Lestari, Intan Ayu, Putra, I Made Rhamandana, Fatimah, Nurul, Ujiantari, Navista Sri Octa, Putri, Dyaningtyas Dewi Pamungkas, Hermawan, Adam
• Format: Journal Article
• Language: English
• Published: Thailand West Asia Organization for Cancer Prevention 01.05.2024
• Subjects: Antineoplastic Agents, Immunological - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Camphanes - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Computational Biology - methods; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Molecular Docking Simulation; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Trastuzumab - pharmacology; Tumor Cells, Cultured; targeted therapy; breast cancer; Trastuzumab Resistant; HER2; Borneol
• ISSN: 1513-7368; 2476-762X
• DOI: 10.31557/APJCP.2024.25.5.1623

The long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance. Borneol (BOR) exerts anticancer effects on various types of cancer. However, its anticancer effect on HER2+ BC remains unknown. This study aimed to determine the potential target genes of BOR and its effect on overcoming the resistance of HER2+ BC to TRZ. The hub gene of  BOR's potential target on HER2+ BC cells was determined via a bioinformatics approach. Resistant HCC1954 cells (HCC1954-TR) were obtained through repeated inducement of HCC1954 cancer cells with TRZ. The cells were then subjected to cytotoxic tests involving single compounds and their combinations. Then, the hub gene expression was determined using quantitative reverse-transcription polymerase chain reaction. The interaction between BOR and selected proteins was measured through molecular docking. Hub genes IL6, TNF, ESR1, IL1B, CYP19A1, AR, NR3C1, RELA, CYP17A1, and GPT were obtained via a bioinformatics approach. HCC1954-TR cells were successfully established. The TRZ-BOR combination treatment of parental HCC1954 (400 µg/mL and 25 µM) and HCC1954-TR (800 µg/mL and 100 µM) yielded considerably better results compared with BOR or TRZ alone. The expressions of AR, GPT, and ESR1 under the TRZ-BOR combination were notably different compared with those under single exposure. The molecular docking study of CYP19A1, CYP17A1, NR3C1, and IL-1β highlighted the potential interaction between BOR and such proteins. BOR improved the cytotoxic effects of TRZ on HCC1954 and HCC1954-TR cell lines, where it specifically targets AR, ESR1, and GPT genes. In addition, the BOR effect, which counteracted the resistance of HCC1954-TR cells to TRZ, was mediated by genes CYP19A1, CYP17A1, NR3C1, IL-1, and RELA. However, additional research is required to validate their role in BOR activity to circumvent the resistance of HER2+ BC to TRZ.