Modification of <i>BRCA1</i>-Associated Breast and Ovarian Cancer Risk by <i>BRCA1</i>-Interacting Genes

Rebbeck, Timothy R.; Mitra, Nandita; Domchek, Susan M.; Wan, Fei; Friebel, Tara M.; Tran, Teo V.; Singer, Christian F.; Tea, Muy Kheng; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie; Garber, Judy E.; Antoniou, Antonis C.; Peock, Susan; Evans, D. Gareth; Paterson, Joan; Kennedy, Michael J.; Donaldson, Alan; Dorkins, Huw; Easton, Douglas F.; Rubinstein, Wendy S.; Daly, Mary B.; Isaacs, Claudine; Nevanlinna, Heli; Couch, Fergus J.; Andrulis, Irene L.; Freidman, Eitan; Laitman, Yael; Ganz, Patricia A.; Tomlinson, Gail E.; Neuhausen, Susan L.; Narod, Steven A.; Phelan, Catherine M.; Greenberg, Roger A.; Nathanson, Katherine L.

doi:10.1158/0008-5472.can-11-0773

Cited by 52 publications

(36 citation statements)

References 25 publications

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“…Recent studies suggest that certain mutations or polymorphisms in the RAP80, ABRA1, or MERIT40/NBA1 (another member of the RAP80 complex) genes are associated with increased susceptibility to breast and/or ovarian cancer (75-80). In addition, the genomic region containing the RAP80 gene is not infrequently lost in TNBCs, which commonly exhibit gross manifestations of genomic instability (81).…”

Section: Discussionmentioning

confidence: 99%

PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair

et al. 2014

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BRCA1 promotes homologous recombination-mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka. PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and down-modulates its function. Moreover, RAP80 contains a poly-ADP-ribose (PAR) interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1-BRCA1-RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft (PDX) models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in BRCA1+/+ individuals.

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Section: Discussionmentioning

confidence: 99%

PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair

et al. 2014

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“…DSBs activate a DNA damage response (DDR) that coordinates the activation of cell cycle checkpoints, apoptosis, and DNA repair networks, to ensure accurate repair and genomic integrity. Defects in DNA repair mechanisms are associated with various human developmental and immune disorders and an increased cancer risk (2–5). …”

Section: Introductionmentioning

confidence: 99%

“…Its role in DDR and the potential link between RAP80 mutations and human mammary and ovarian cancer, suggested that defective RAP80 function/expression might result in genomic instability and increased cancer risk (5, 21). In this study, we investigated the effect of the loss of RAP80 expression on genomic stability and cancer development in RAP80 −/− mice using several tumorigenesis models, including IR-induced lymphoma and 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary cancer.…”

Section: Introductionmentioning

confidence: 99%

RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development

et al. 2012

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The ubiquitin interaction motif (UIM)-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci (IRIF). In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80−/−) mice. RAP80−/− mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEFs) derived from RAP80−/− mice underwent premature senescence compared to wild type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80−/− thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80−/− mice were more susceptible to spontaneous lymphoma development and the development of DMBA-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53−/− and p53+/− mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function.

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“…Although several studies have assessed the role of the most common ATM variants in breast cancer susceptibility, the results obtained are inconsistent [35]. A recent study had identified an association between an ATM haplotype and breast cancer risk in BRCA1 mutation carriers with a false discovery rate-adjusted p value of 0.029 for overall association of the haplotype [36]. Four of the five SNPs making up the haplotype were almost perfectly correlated ( r 2 >0.9) with the three originally genotyped SNPs of the present study.…”

Section: Discussionmentioning

confidence: 99%

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Hamdi¹,

Soucy²,

Kuchenbaeker³

et al. 2016

Breast Cancer Res Treat

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PurposeCis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.MethodsUsing data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ∼320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.ResultsWe identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.ConclusionWe identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

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Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes

Cited by 52 publications

References 25 publications

PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair

PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair

RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

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