Francesca Pia Carbone, Pietro Ancona, Stefano Volinia, Anna Terrazzan, Nicoletta Bianchi
{"title":"Druggable Molecular Networks in <i>BRCA1/BRCA2</i>-Mutated Breast Cancer.","authors":"Francesca Pia Carbone, Pietro Ancona, Stefano Volinia, Anna Terrazzan, Nicoletta Bianchi","doi":"10.3390/biology14030253","DOIUrl":null,"url":null,"abstract":"<p><p>Mutations in the tumor suppressor genes <i>BRCA1</i> and <i>BRCA2</i> 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 <i>BRCA1</i> and <i>BRCA2</i> 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 <i>BRCA</i> mutations, and 24 were modulated by therapies. In particular, <i>BIRC5</i>, <i>SIRT1</i>, <i>MYC</i>, <i>EZH2</i>, and <i>CSN2</i> are influenced by <i>BRCA1</i>, while <i>BCL2</i>, <i>BAX</i>, and <i>BRIP1</i> are influenced by <i>BRCA2</i> mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only <i>BRCA1</i>/<i>BRCA2</i>-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 <i>BIRC5</i> while it increased <i>SIRT1</i> both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in <i>BRCA</i>-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.</p>","PeriodicalId":48624,"journal":{"name":"Biology-Basel","volume":"14 3","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940086/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biology-Basel","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/biology14030253","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Biology (ISSN 2079-7737) is an international, peer-reviewed, quick-refereeing open access journal of Biological Science published by MDPI online. It publishes reviews, research papers and communications in all areas of biology and at the interface of related disciplines. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.