Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1

Cantor, Sharon B.; Guillemette, Shawna

doi:10.2217/fon.10.191

Cited by 93 publications

(85 citation statements)

References 80 publications

(67 reference statements)

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“…Multiple germline mutations that disrupt Bach1 enzyme activity or BRCA1 association have been identified in breast cancer indicating Bach1 is a tumor suppressor [89]. Recently a frame shift mutations in the Bach1 gene that greatly affect the risk of invasive ovarian cancer has also been identified in ovarian cancer [91].…”

Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

“…In addition, depletion of Bach1 by siRNAs was also shown to compromise HR [82,86]. Bach1 enzyme activity as well as the BRCA1-FancJ interaction is essential for DNA repair, checkpoint activation and tumor suppression [29,89,90].Multiple germline mutations that disrupt Bach1 enzyme activity or BRCA1 association have been identified in breast cancer indicating Bach1 is a tumor suppressor [89]. Recently a frame shift mutations in the Bach1 gene that greatly affect the risk of invasive ovarian cancer has also been identified in ovarian cancer [91].…”

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confidence: 99%

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BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

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Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

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confidence: 99%

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BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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“…Diet is one of the modifiable risk factors, together with adiposity, physical activity, smoking, alcohol consumption, and the use of hormonal replacement therapy (Mahoney et al, 2008;Romieu, 2011). Heterozygous carriers of mutations in the hereditary breast cancer genes BRCA1 or BRCA2 have a 60-80% lifetime risk of breast cancer (Cantor and Guillemette, 2011).…”

Section: Breast Cancermentioning

confidence: 99%

Repercussions of Breastfeeding by Diabetic Women for Breast Cancer

França

França-Botelho²,

França³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Diabetes represents a serious health problem. In the diabetic state, alterations in metabolism, increased susceptibility to infections and immunological changes occur. The suppression of the immune response has been identified as a relevant factor that contributes to the increase in the rate of infections in these patients. At the same time, breast cancer is the most frequent malignant tumor in women. The molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Breastfeeding has been hypothesized to reduce the risk of breast cancer. However, early systematic reviews have not yielded consistent findings for this association. The demand for human milk is increasing due to the promotion and consumer acceptance of the health benefits of consuming a natural product rich in bioactive components. However, due to changes in glucose metabolism, the components of the milk from diabetic women are modified depending on the time of evaluation. In this literature review, we summarize important new findings revealing the paradoxical role of breastfeeding in preventing the onset of breast cancer in diabetic mothers. We hypothesized that the milk component production in diabetic mothers is affected by changes in glucose metabolism. Therefore, adequate maternal glycemic control and an adequate duration of breastfeeding for diabetic mothers are crucial to ensure that the immunity components are able to confer protection against breast cancer.

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“…This BRCA1/BACH1 complex can transiently inhibit DNA synthesis and participate in error-free HR-mediated DNA repair in order to resume progression of the stalled fork [173]. Mutations in BRCA1 or BACH1 that inhibit their complex formation render cells unable to participate in HR-mediated repair and are associated with an increased risk for breast cancer [118], [174]- [177].…”

Section: Genome Instability Is Triggered By Replication Stressmentioning

confidence: 99%

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

Nelson

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Ras proteins function as molecular signaling switches that can stimulate multiple mitogenic pathways in response to extracellular signaling. Oncogenic activation of Ras by structural mutation is a highly transforming event in ~1/3 of human cancers. However, aberrant Ras activation can also promote oncogene-induced senescence. This Rasinduced irreversible growth arrest is a physiological process that acts as a barrier to malignancy. The mechanisms by which Ras drives senescence and how this process is bypassed during Ras-driven transformation remains poorly understood.Although mutations in the RAS gene are extremely rare in human breast cancer, the Ras signaling pathway is constitutively activated in roughly half of all primary breast tumors. This is largely due to aberrant activation of upstream regulators of Ras, like the EGFR family member Her2 and inactivation of negative Ras regulators, such as NF1.NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and senescence. Expression of NORE1A is frequently lost in primary breast tumors and breast cancer cell lines, though its mechanism of action in breast cancer pathogenesis remains unclear. vi BRCA1 is a tumor suppressor that plays a key role in DNA DSB repair. Loss of BRCA1 is associated with hereditary breast and ovarian cancer, and is also thought to play a role in sporadic breast cancer. Recently, BRCA1 was shown to play a role in both Her2 and Ras senescence, but the mechanism underlying the communication between Her2/Ras and BRCA1 was not identified.I have discovered that NORE1A forms an endogenous, Her2/Ras-regulated complex with BRCA1. I show that dual suppression of NORE1A and BRCA1 has a synergistic effect on transformation. Furthermore, I show that NORE1A loss suppresses the BRCA1-mediated senescence effect. Finally, I show that NORE1A and BRCA1 synergize to modulate DNA repair. Thus, I identify a novel tumor suppressor complex that connects Her2/Ras senescence signaling to BRCA1 in breast cancer. GAPs stabilize the catalytic machinery of Ras, enhancing its intrinsic ability to hydrolyze GTP into GDP and returning Ras to its inactive conformation.5 In addition to mitogenic signaling, activated Ras can also drive apoptosis and senescence.Ras signaling through Raf can promote p53-mediated apoptosis, and has also been implicated in senescence induction via p21 and p16. Ras-mediated activation of RASSF1A leads to apoptosis via activation of pro-apoptotic BAX proteins, or by activation of the pro-apoptotic Hippo pathway via phosphorylation of the MST kinases.RASSF1A has also been reported to drive senescence via p53-independent regulation of p21. Ras-mediated activation of NORE1A can promote p53-dependent upregulation of p21 to drive cell cycle arrest or senescence.12 Ras growth inhibitory effectorsThe RASSF familyThere are ten RASSF family members (along with various isoforms), which are now split into two groups: the "classical" members (RASSF1-6), which contain an RA domain and a SARAH domain at their C-term...

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Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1

Cited by 93 publications

References 80 publications

BRCA1 tumor suppressor network: focusing on its tail

BRCA1 tumor suppressor network: focusing on its tail

Repercussions of Breastfeeding by Diabetic Women for Breast Cancer

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

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