KEY TAKEAWAYS
- The study aimed to explore REG3A’s expression and functions in TNBC, identifying potential new targets.
- The results revealed that ZNF680-triggered REG3A overexpression promotes breast cancer tumorigenesis via Akt-mTOR activation, suggesting a promising therapeutic target.
In the quest to uncover fresh targets for triple-negative breast cancer (TNBC), thorough scrutiny has been directed towards REG3A (regenerating islet-derived protein 3 A), a lectin protein reliant on calcium. Its expression and roles in breast cancer have been extensively examined.
Xiaoxia Jin and the team aimed to investigate REG3A expression and functions in TNBC to identify potential therapeutic targets.
Bioinformatics and local tissue analyses were used to detect REG3A expression in breast cancer. Researchers employed genetic techniques to modify REG3A expression and observed its effects on breast cancer cell behavior. Subcutaneous xenograft models were established to explore REG3A’s role in breast cancer cell growth in vivo.
The results revealed elevated REG3A levels in human breast cancer tissues, as uncovered by analysis of the TCGA database. Furthermore, both REG3A mRNA and protein levels were heightened in locally treated TNBC tissues compared to adjacent normal tissues.
In primary human TNBC cells, REG3A knockdown significantly impeded cell proliferation, migration, and invasion while promoting caspase-mediated apoptosis. Similarly, utilizing CRISPR-sgRNA for REG3A knockout demonstrated notable anti-TNBC cell activity.
Conversely, REG3A overexpression enhanced cell proliferation and migration. REG3A was found to be crucial for activating the Akt-mTOR cascade, evidenced by reduced Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression.
A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the inhibition of proliferation and induction of apoptosis induced by REG3A knockdown in breast cancer cells. Additionally, REG3A played a pivotal role in maintaining mTOR complex integrity. Bioinformatics analysis identified zinc finger protein 680 (ZNF680) as a potential transcription factor for REG3A.
Knockdown or knockout of ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells.
In vivo experiments demonstrated that REG3A knockdown significantly inhibited primary TNBC cell xenograft growth. Reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident in REG3A-silenced xenograft tissues.
The study concluded that ZNF680-induced REG3A overexpression may contribute to breast cancer tumorigenesis by potentially stimulating Akt-mTOR activation, highlighting its promise as an innovative cancer target.
Funding was provided by the Science and Technology Project of NanTong.
Source: https://pubmed.ncbi.nlm.nih.gov/38840145/
Jin X, Yang S, Lu X, et al. (2024). “Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.” Breast Cancer Res. 2024 Jun 5;26(1):92. doi: 10.1186/s13058-024-01845-2. PMID: 38840145.
