Insights into the functions of BRCA1 and BRCA2

Welcsh, Piri; Owens, Kelly N.; King, Mary Claire

doi:10.1016/s0168-9525(99)01930-7

Cited by 304 publications

(241 citation statements)

References 59 publications

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“…b Multivariate linear regression included terms for age (years), BMI (kg m À2 ), current smoker (yes/no), alcohol intake (total drinks of per day), physical activity (total hours of per week), and total daily caloric intake (kcal). that were differentially expressed, included the downregulation of RAD51, which encodes a protein known to interact with BRCA1 and participates in the repair of DNA double strand breaks (Welcsh et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

et al. 2007

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The BRCA1 gene product helps to maintain genomic integrity through its participation in the cellular response to DNA damage: specifically, the repair of double-stranded DNA breaks. An impaired cellular response to DNA damage is a plausible mechanism whereby BRCA1 mutation carriers are at increased risk of breast cancer. Hence, an individual's capacity to repair DNA may serve as a useful biomarker of breast cancer risk. The overall aim of the current study was to identify a biomarker of DNA repair capacity that could distinguish between BRCA1 mutation carriers and non-carriers. DNA repair capacity was assessed using three validated assays: the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of g-H2AX nuclear foci. DNA repair capacity of peripheral blood lymphocytes from 25 cancer-free female heterozygous BRCA1 mutation carriers and 25 noncarrier controls was assessed at baseline and following cell exposure to g -irradiation (2 Gy). We found no significant differences in the mean tail moment, in the number of micronuclei or in the number of g-H2AX nuclear foci between the carriers and non-carriers at baseline, and following g-irradiation. These data suggest that these assays are not likely to be useful in the identification of women at a high risk for breast cancer. British Journal of Cancer (2007) The inheritance of a deleterious mutation in the breast cancer susceptibility gene, BRCA1, has been associated with a lifetime risk of breast cancer of between 45 and 87% (Ford et al, 1998;Antoniou et al, 2003). Genetic, reproductive, and environmental factors have all been suggested to influence breast cancer risk in BRCA1 mutation carriers (reviewed in Narod and Offit (2005)). The use of breast cancer as an endpoint to evaluate the protective role of potential modifying factors is not always feasible. Thus, there is a need to ascertain biomarkers of cancer susceptibility in these women. In turn, the identification of a valid biomarker of breast cancer risk would allow us to identify mutation carriers and help improve our ability to target, and to evaluate the effect of both dietary and lifestyle alterations, as well as, medical diagnostic and therapeutic interventions on breast cancer risk.The BRCA1 protein plays a vital role in maintaining genomic stability because of its key role in the repair of double-stranded DNA breaks by homologous recombination (reviewed in Welcsh et al (2000)). If double-stranded DNA breaks are left unrepaired, or are repaired inaccurately, aberrant chromosome breaks, deletions, and translocations may accumulate. Thus, an impaired cellular response to DNA damage appears to be a plausible mechanism whereby BRCA1 mutation carriers are at an increased risk of breast cancer (Scott, 2004). Hence, the evaluation of an individual's capacity to repair DNA may serve as a biomarker of breast cancer risk in carriers of these mutations.Two previous studies have shown higher levels of chromosomal aberrations and chromosomal breaks among women with a BRCA...

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Section: Discussionmentioning

confidence: 99%

“…The BRCA1 protein plays a vital role in maintaining genomic stability because of its key role in the repair of double-stranded DNA breaks by homologous recombination (reviewed in Welcsh et al (2000)). If double-stranded DNA breaks are left unrepaired, or are repaired inaccurately, aberrant chromosome breaks, deletions, and translocations may accumulate.…”

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DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

et al. 2007

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“…5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint. 7 In addition, the ubiquitin ligase activity of the BRCA1-BARD1 complex has been described. 8 Somatic mutations of BRCA1 and BRCA2 appear to be very rare, 9 -12 but loss of heterozygosity of BRCA1 and BRCA2 is frequently observed, suggesting involvement of these genes in the pathogenesis of sporadic breast cancers.…”

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confidence: 99%

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

Egawa

Miyoshi

Taguchi

et al. 2002

Intl Journal of Cancer

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The prognostic significance of BRCA 2 mRNA levels in tumor tissues was studied in sporadic breast cancer patients. BRCA 2 mRNA levels were determined by real-time PCR. Histologic grade III tumors showed significantly (p ‫؍‬ 0.001) higher BRCA 2 mRNA levels (0.828 ؎ 0.102 BRCA 2/␤-glucuronidase mRNA ratio, mean ؎ SE) than histologic grade I and II tumors (0.438 ؎ 0.055) and estrogen receptor (ER)-negative tumors (0.773 ؎ 0.102) showed a nonsignificant (p ‫؍‬ 0.072) trend toward an increase in BRCA 2 mRNA levels compared to ER-positive tumors (0.541 ؎ 0.079). Other clinicopathologic parameters, such as menopausal status, lymph node status and tumor size, were not significantly associated with BRCA 2 mRNA levels. Patients with high BRCA 2 mRNA levels showed a significantly (p ‫؍‬ 0.006) lower 5-year disease free survival rate (63%) than those with low levels (94%). Lymph node metastases, ER negativity and high histologic grade were also significantly (p < 0.05) associated with poor prognosis. Multivariate analysis revealed that BRCA 2 mRNA levels were a significant prognostic factor, being independent of the other conventional prognostic factors. Our results suggest that BRCA 2 mRNA levels might serve as a clinically useful prognostic factor in breast cancer patients. © 2002 Wiley-Liss, Inc. Key words: breast cancer; BRCA2; prognosis; ER; histologic grade BRCA1 and BRCA2 are the well-established breast cancer susceptibility genes and germline mutations of these genes are found in 20 -30% of breast cancer families. 1-4 BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint. 7 In addition, the ubiquitin ligase activity of the BRCA1-BARD1 complex has been described. 8 Somatic mutations of BRCA1 and BRCA2 appear to be very rare, 9 -12 but loss of heterozygosity of BRCA1 and BRCA2 is frequently observed, suggesting involvement of these genes in the pathogenesis of sporadic breast cancers. BRCA1 mRNA levels are downregulated in sporadic breast cancers compared to normal breast tissues and hypermethylation of the promoter region of BRCA1 explains this downregulation in some cases. 13,14 However, BRCA2 mRNA levels do not show a consistent tendency and are both upregulated and downregulated among sporadic breast cancers. 15 Unlike BRCA1, the promoter region of BRCA2 is not hypermethylated. 16 Thus, the contributions of BRCA1 and BRCA2 to the pathogenesis of sporadic breast cancers might be different.Downregulation of BRCA1 mRNA and protein levels is associated with an aggressive phenotype of sporadic breast cancers 17,18 and poor prognosis. 19 In contrast, Bieche et al. 15 reported that high BRCA2 mRNA levels are associated with an aggressive phenotype of sporadic breast cancer. We have...

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“…Subsequently, Stat5 deregulation may modulate cyclin D1 control of cell-cycle progression by direct interaction with its binding site in the cyclin D1 promoter, or inhibit apoptosis by inducing NF-kB activation via RANK-L (Hynes, 2002;Hennighausen and Robinson, 2005). A third possibility for Stat5 tumorigenic activity involves its interacting proteins, many of which have been implicated in cancer [GR (Wu et al, 2005), TRb1 (Cheng, 2003), BRCA1 and BRCA2 (Welcsh et al, 2000), ERK (Santen et al, 2002), Nmi Jung et al, 2005), SMRT (Keeton and Brown, 2005), CBP (Iwase, 2003), STAP-2/BKS (Yamamoto et al, 2003), NCoA-1/ SRC-1 (Xu and Li, 2003;Shah and Rowan, 2005), p100, Oct-1 , and ERa (Yamashita and Iwase, 2002)]. Deregulated expression of each of these proteins may also alter Stat5 activity and trigger tumorigenesis.…”

Section: Mouse Models For Stat5 Involvement In Breast Cancermentioning

confidence: 99%

Stat5 in the mammary gland: Controlling normal development and cancer

Barash

2006

Journal Cellular Physiology

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The signal transducer and activator of transcription (Stat5) funnels extracellular signals of cytokines, hormones, and growth factors into transcriptional activity in the mammary gland. Postnatal development and functionality of this tissue is synchronized with the reproductive cycle. Consequently, Stat5 involvement in lobuloalveolar development, milk-protein synthesis, or tissue remodeling is dictated by the particular reproductive stage. Latent deregulation of Stat5 activity during the reproductive cycle predisposes the tissue to tumorigenesis at a later stage, when the female is no longer fertile. Accumulating data from studies with mouse models and breast-cancer specimens demonstrate a dual role for Stat5 in this context. It causes tumorigenesis, but delays metastasis progression. Consequently, Stat5 activity in breast-cancer specimens marks a better prognosis for survival.

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Insights into the functions of BRCA1 and BRCA2

Cited by 304 publications

References 59 publications

DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

Stat5 in the mammary gland: Controlling normal development and cancer

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