DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-06-14

AUTHORS

Tereza Vaclová, Gonzalo Gómez-López, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Javier Benítez, Ana Osorio

ABSTRACT

BRCA1 germline mutations increase the lifetime risk of developing breast and ovarian cancers. However, taking into account the differences in disease manifestation among mutation carriers, it is probable that different BRCA1 mutations have distinct haploinsufficiency effects and lead to the formation of different phenotypes. Using lymphoblastoid cell lines derived from heterozygous BRCA1 mutation carriers and non-carriers, we investigated the haploinsufficiency effects of various mutation types using qPCR, immunofluorescence, and microarray technology. Lymphoblastoid cell lines carrying a truncating mutation showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or those harboring a missense mutation, indicating greater spontaneous DNA damage. Cells carrying either BRCA1 mutation type showed impaired RAD51 foci formation, suggesting defective repair in mutated cells. Moreover, compared to controls, cell lines carrying missense mutations displayed a more distinct expression profile than cells with truncating mutations, which is consistent with different mutations giving rise to distinct phenotypes. Alterations in the immune response pathway in cells harboring missense mutations point to possible mechanisms of breast cancer initiation in carriers of these mutations. Our findings offer insight into how various heterozygous mutations in BRCA1 could lead to impairment of BRCA1 function and provide strong evidence of haploinsufficiency in BRCA1 mutation carriers. More... »

PAGES

271-282

Journal

TITLE

Breast Cancer Research and Treatment

ISSUE

2

VOLUME

152

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10549-015-3459-3

DOI

http://dx.doi.org/10.1007/s10549-015-3459-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1002354354

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26071757


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