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INTERNATIONAL CONGRESS OF

CancerGenetics

• Gene Editing Strategies for Reactivation of BRCA1/2 in Breast Cancer

• Ali Rezaei,¹ Paria sadat Aghaseyedmirzaei,² Shirin Farivar,^3,*
  1. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  3. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
  
  
  
• Introduction: Breast cancer exists as one of the leading cancer types worldwide because BRCA1 and BRCA2 gene mutations in both germline and somatic cells drive hereditary and sporadic breast cancer development. The tumor suppressors function as essential components for the homologous recombination repair (HRR) breaks. The absence of BRCA1/2 function creates genomic instability, chromosomal rearrangements, and increased cancer development risk. The therapeutic effect of PARP inhibitors against BRCA-deficient cancer cells becomes less effective when patients develop resistance to these treatments. The development of CRISPR/Cas9 gene editing technology along with base editors and prime editors, provides scientists with new ways to restore BRCA1/2 gene function in breast cancer patients. This review investigates methods to reactivate BRCA1/2 in breast cancer through discussions of experimental results, their preclinical outcomes, and translation challenges.
• Methods: The research examined studies from 2020 onward that used CRISPR-based and alternative gene editing methods to repair BRCA1/2 function in breast cancer models. The literature search included studies that used site-specific editing to modify BRCA1 exon 11, BRCA2 exon 27, and the most common mutation hotspots BRCA1 185delAG and BRCA2 6174delT. The research included both laboratory cell line studies using MDA-MB-436 and HCC1937 triple-negative breast cancer cells and animal studies using xenograft mouse models. The research focused on three key aspects, which included editing precision, delivery methods, and combination effects with targeted cancer treatments.
• Results: 1. CRISPR-based correction of BRCA1/2 frameshift mutations The research shows that CRISPR/Cas9-mediated homology-directed repair (HDR) successfully fixes pathogenic deletions like BRCA1 185delAG and BRCA2 6174delT in breast cancer cell lines. The cells regained their ability to form RAD51 foci, which showed that homologous recombination functioned again and made them more responsive to DNA-damaging chemotherapy. 2. Base and prime editing for hotspot mutations Base editors and prime editors provide single-nucleotide editing, which solves the conventional CRISPR/Cas9 problem, which breaks the DNA double-strand. Scientists have fixed BRCA1 c.4035delA and BRCA2 c.5946delT mutations within patient-derived organoids. These approaches restored CHK2 phosphorylation and p53 activation, which are key downstream pathways of DNA damage response. 3. Synthetic lethality reversal and therapy resistance The recovery of BRCA1/2 gene function leads to changes in cells' response to PARP inhibitor treatment. The CRISPR-based correction of BRCA1 exon 11 in triple-negative breast cancer cells made these cells resistant to olaparib treatment, which shows that BRCA reactivation changes therapeutic strategy. The research shows that BRCA reactivation needs to be combined with ATR inhibitors and immune checkpoint blockade for effective treatment. 4. Delivery challenges and innovations One problem is the efficient delivery throughout the breast tumor microenvironment Scientists achieved targeted delivery of BRCA1-editing tools to HER2-positive breast cancer xenografts through the use of lipid nanoparticles (LNPs) that carried HER2-targeting ligands. The use of adeno-associated virus 9 (AAV9) vectors with tumor-specific promoters demonstrated effective off-target expression control in normal tissues. 5. Preclinical outcomes and translational prospects The treatment of BRCA1-mutant breast tumors in mouse models through nanoparticle-delivered CRISPR-Cas9 resulted in a 60% decrease in tumor growth and extended life expectancy compared to untreated mice. The restoration of BRCA2 function led to decreased chromosomal abnormalities and reduced genomic instability. The use of Cas proteins in CRISPR-Cas9 therapy faces three main challenges, which include immune system reactions to Cas proteins, gene editing persistence, and ethical issues of edited gene transmission.
• Conclusion: The genetic modification technique of gene editing enables scientists to reactivate BRCA1/2 genes in breast cancer patients by directly addressing the DNA repair system defects that cause the disease. CRISPR/Cas9-mediated HDR, base editing, and prime editing have shown their ability to restore BRCA1/2 function in laboratory cell cultures and animal studies. The path to clinical application faces several challenges, which involve improving delivery precision, reducing off-target effects, and determining optimal treatment protocols following gene reactivation. The integration of BRCA1/2 restoration into precision oncology systems has the potential to transform cancer treatment by moving beyond using BRCA deficiency for therapy and toward permanent tumor control through functional gene repair.
• Keywords: BRCA1, BRCA2, Breast Cancer, CRISPR, Gene Editing