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Druggable Molecular Networks in BRCA1/BRCA2-Mutated Breast Cancer
Francesca Pia Carbone1, Pietro Ancona1, Stefano Volinia1,2,3
1Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
Abstract:
Mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with the triple-negative breast cancer phenotype, particularly aggressive and hard-to-treat tumors lacking estrogen, progesterone, and human epidermal growth factor receptor 2. This research aimed to understand the metabolic and genetic links behind BRCA1 and BRCA2 mutations and investigate their relationship with effective therapies. Using the Cytoscape software, two networks were generated through a bibliographic analysis of articles retrieved from the PubMed-NCBI database. We identified 98 genes deregulated by BRCA mutations, and 24 were modulated by therapies. In particular, BIRC5, SIRT1, MYC, EZH2, and CSN2 are influenced by BRCA1, while BCL2, BAX, and BRIP1 are influenced by BRCA2 mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only BRCA1/BRCA2-mutated cells. In this context, CDDO-Imidazolide was shown to increase ROS levels and induce DNA damage. Similarly, resveratrol decreased the expression of the anti-apoptotic gene BIRC5 while it increased SIRT1 both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in BRCA-mutated cells or block cell growth when the mutation occurs, i.e., 3-deazaneplanocin A, genistein or daidzein, and PARP inhibitors. Finally, over-representation analysis on the genes highlights ferroptosis and proteoglycan pathways as potential drug targets for more effective treatments.
Insights
BRCA1 and BRCA2 mutations drive aggressive triple-negative breast cancer. This study identifies deregulated genes and therapies, highlighting ferroptosis and proteoglycan pathways as potential drug targets for improved treatment outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mutations in tumor suppressor genes BRCA1 and BRCA2 are linked to aggressive triple-negative breast cancer (TNBC).
- TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth factor receptor 2, making it difficult to treat.
Purpose of the Study:
- To elucidate the metabolic and genetic connections underlying BRCA1/BRCA2 mutations.
- To explore the relationship between these mutations and effective therapeutic strategies.
- To identify novel drug targets for BRCA-mutated cancers.
Main Methods:
- Bibliographic analysis of PubMed-NCBI articles using Cytoscape software to construct gene networks.
- Identification of genes deregulated by BRCA mutations and modulated by therapies.
- Evaluation of the efficacy of targeted therapies in BRCA1/BRCA2-mutated cells.
Main Results:
- 98 genes were found to be deregulated by BRCA mutations, with 24 modulated by therapies.
- Specific genes like BIRC5, SIRT1, MYC, EZH2, CSN2 (BRCA1) and BCL2, BAX, BRIP1 (BRCA2) were identified.
- Therapies such as CDDO-Imidazolide, resveratrol, 3-deazaneplanocin A, genistein, daidzein, and PARP inhibitors showed selective efficacy against BRCA-mutated cells.
- Ferroptosis and proteoglycan pathways emerged as potential therapeutic targets.
Conclusions:
- BRCA1/BRCA2 mutations create vulnerabilities that can be exploited by targeted therapies.
- Understanding gene networks and pathway alterations is crucial for developing effective treatments for TNBC.
- Ferroptosis and proteoglycan pathways represent promising avenues for future drug development in BRCA-mutated cancers.
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