Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MERIT40 is a recently identified BRCA1 and RAP80 interacting protein that is essential for protein-protein interactions of a BRCA1 complex also containing Abraxas, BRCC36 and BRCC45. It is a mediator of checkpoint functions and DNA damage signaling through a (de)ubiquitination cascade. Based on its interaction with BRCA1 and its role in genome integrity maintenance, MERIT40 is a novel candidate gene for being involved in hereditary susceptibility to breast cancer. Here, we report to our knowledge the first comprehensive mutation screening of this gene in affected cases of breast cancer families. Only a number of sequence variants were found, four of which are novel. None of the observed variants appeared to be disease related, suggesting that germline mutations in MERIT40 are rare or absent in familial breast cancer patients.
Breast Cancer Res Treat 2010 Feb
PMID:Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families. 1957 97

LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.
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PMID:Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. 1964 67

Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein essential for the ATR and CHK1-dependent checkpoint elicited by replicative stress or the presence of ssDNA. Here, we describe a study to determine whether mutational disruption of CLSPN contributes to cancer susceptibility and sporadic tumorigenesis. We resequenced CLSPN from the germline of selected cancer families with a history of breast cancer (n = 25) or a multicancer phenotype (n = 46) as well as from a panel of sporadic cancer cell lines (n = 52) derived from a variety of tumor types. Eight nonsynonymous variants, including a recurrent mutation, were identified from the germline of two cancer-prone individuals and five cancer cell lines of breast, ovarian, and hematopoietic origin. None of the variants was present within population controls. In contrast, mutations were rare within genes encoding the CLSPN-interacting protein ATR and its binding partner ATRIP. One variant of CLSPN, encoding the I783S missense mutation, was defective in its ability to mediate CHK1 phosphorylation following DNA damage and was unable to rescue sensitivity to replicative stress in CLSPN-depleted cells. Taken together, these observations raise the possibility that CLSPN may encode a component of the DNA-damage response pathway that is targeted by mutations in human cancers, suggesting the need for larger population-based studies to investigate whether CLSPN variants contribute to cancer susceptibility.
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PMID:Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin. 1973 71

Loss of expression of the type III transforming growth factor-beta receptor (TbetaRIII or betaglycan), a transforming growth factor-beta (TGF-beta) superfamily co-receptor, is common in human breast cancers. TbetaRIII suppresses cancer progression in vivo by reducing cancer cell migration and invasion by largely unknown mechanisms. Here, we demonstrate that the cytoplasmic domain of TbetaRIII is essential for TbetaRIII-mediated downregulation of migration and invasion in vitro and TbetaRIII-mediated inhibition of breast cancer progression in vivo. Functionally, the cytoplasmic domain of TbetaRIII is required to attenuate TGF-beta signaling, whereas TbetaRIII-mediated attenuation of TGF-beta signaling is required for TbetaRIII-mediated inhibition of migration and invasion. Mechanistically, both TbetaRIII-mediated inhibition of TGF-beta signaling and TbetaRIII-mediated inhibition of invasion occur through the interaction of the cytoplasmic domain of TbetaRIII with the scaffolding protein GAIP-interacting protein C-terminus (GIPC). Taken together, these studies support a functional role for the TbetaRIII cytoplasmic domain interacting with GIPC to suppress breast cancer progression.
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PMID:The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling. 1995 93

Cell cycle regulatory pathways in breast cancer are incompletely described. Here, we report an important role in estrogen receptor alpha (ERalpha)-positive breast cancer cells for the protein kinase C1 (PKC1)-interacting protein RBCK1 in supporting cell cycle progression by driving transcription of ERalpha and cyclin B1. RBCK1-depleted cells exhibited increased accumulation in G(2)-M phase of the cell cycle, decreased proliferation, and reduced mRNA levels for ERalpha and its target genes cyclin D1 and c-myc. Chromatin immunoprecipitation revealed that ERalpha transcription is associated with RBCK1 recruitment to the ERalpha promoter, suggesting that transcriptional regulation is one mechanism by which RBCK1 affects ERalpha mRNA levels. G(2)-M phase arrest was mediated independently from reduced ERalpha levels, instead associated with transcriptional inhibition of the key G(2)-M regulator cyclin B1. In breast tumor samples, there was a positive correlation between levels of RBCK1, ERalpha, and cyclin B1 mRNA levels. Our findings suggest that RBCK1 regulates cell cycle progression and proliferation of ERalpha-positive breast cancer cells by supporting transcription of ERalpha and cyclin B1.
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PMID:RBCK1 drives breast cancer cell proliferation by promoting transcription of estrogen receptor alpha and cyclin B1. 2010 25

Insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling participates in a variety of cellular processes, including cell survival, growth, and proliferation. Increased expression of IGF-1R and activation of its downstream signaling components have been implicated in human cancers. Although a regulatory role for IGF-1R has been established, the relationship between IGF-1R and its binding partner, GAIP-interacting protein C-terminus (GIPC), in terms of promoting cell proliferation, remains unclear. We found that siRNA-mediated silencing of GIPC expression decreased IGF-1-mediated IGF-1R phosphorylation and cellular proliferation in breast cancer models. IGF-1-mediated cellular proliferation was also inhibited by N-acetylcysteine, which implicates reactive oxygen species generation. siRNA-mediated silencing of GIPC expression also decreased IGF-1-mediated reactive oxygen species generation. Taken together, these data suggest that GIPC contributes to IGF-1-induced cancer cell proliferation via the regulation of reactive oxygen species production.
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PMID:GIPC mediates the generation of reactive oxygen species and the regulation of cancer cell proliferation by insulin-like growth factor-1/IGF-1R signaling. 2020 41

The urokinase-type plasminogen activator receptor (uPAR) has diverse biological functions including roles in proteolysis, cell adhesion and cellular signaling. We identified a heat shock protein MRJ (DNAJB6) as a novel uPAR-interacting protein in a yeast two-hybrid screen and confirmed the interaction and co-localization by GST-pull down assays, and co-immunoprecipitation in cells transfected with MRJ. Endogenous interaction between uPAR and MRJ was also detected in breast cancer MDA-MB-231 cells. Deletion mapping demonstrated that the C-terminal region of MRJ is required to mediate its interaction with uPAR. To understand the biological function of the uPAR-MRJ complex, we determined whether MRJ regulated uPAR mediated adhesion to vitronectin in human embryonic kidney (HEK) 293 cells stably transfected with uPAR. After transfection with full length MRJ, there was a 50% increase in cell adhesion compared to the mock transfected control (p<0.01). This increase in adhesion is dependent on the uPAR/full length MRJ interaction as cells transfected with the mutant construct containing only N-terminal region or C-terminal region of MRJ had no increase in cell adhesion. The observed increase in adhesion to vitronectin by MRJ was also blocked by an anti-uPAR domain I antibody suggesting that the induced adhesion is at least in part contributed by uPAR on the cell surface. These data provide a novel mechanism by which uPAR plays a role in cell adhesion to vitronectin.
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PMID:Interaction between urokinase receptor and heat shock protein MRJ enhances cell adhesion. 2037 89

CHFR functions as a mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. CHFR is frequently silenced by hypermethylation in human cancers, indicating that CHFR is a tumor suppressor. To further elucidate the role of CHFR in tumorigenesis, we studied the relationship between CHFR and a novel CHFR-interacting protein, HLTF, helicase-like transcription factor. Here we show that CHFR binds to and ubiquitinates HLTF, leading to its degradation. HLTF modulates basal expression of PAI-1 involved in regulation of cell migration. Consistently, overexpression of CHFR inhibits cell migration, resulting from reduced HLTF followed by decreased PAI-1 expression. HLTF expression is also higher in human breast cancer cells where CHFR is not expressed. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer.
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PMID:CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. 2038 95

Members of the polo-like kinases (Plk1, Plk2, Plk3 and Plk4) are involved in the regulation of various stages of the cell cycle and have been implicated in cancer progression. Unlike its other family members, the expression of Plk3 remains steady during cell cycle progression, suggesting that its activity may be spatiotemporally regulated. However, the mechanism of regulation of Plk3 activity is not well understood. Here, we show that calcium- and integrin-binding protein 1 (CIB1), a Plk3 interacting protein, is widely expressed in various cancer cell lines. Expression of CIB1 mRNA as well as protein is increased in breast cancer tissue as compared to normal tissue. CIB1 constitutively interacts with Plk3 as determined by both in vitro and in vivo assays. This interaction of CIB1 with Plk3 is independent of intracellular Ca(2+). Furthermore, binding of CIB1 results in inhibition of Plk3 kinase activity both in vitro and in vivo. Interestingly, this inhibition of the Plk3 activity by CIB1 is Ca(2+)-dependent. Taken together, our results suggest that CIB1 is a regulatory subunit of Plk3 and it regulates Plk3 activity in a Ca(2+)-dependent manner. Furthermore, upregulation of CIB1 in cancer cells could thus inhibit Plk3 activity leading to abnormal cell cycle regulation in breast cancer cells. Thus, in addition to Plk3, CIB1 may be a potential biomarker and target for therapeutic intervention of breast cancer.
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PMID:Calcium-dependent inhibition of polo-like kinase 3 activity by CIB1 in breast cancer cells. 2047 78

Partner and localizer of BRCA2 (PALB2) was originally identified as a BRCA2-interacting protein that is crucial for key BRCA2 genome caretaker functions. It subsequently became clear that PALB2 was another Fanconi anemia (FA) gene (FANCN), and that monoallelic PALB2 mutations are associated with increased risk of breast and pancreatic cancer. Mutations in PALB2 have been identified in breast cancer families worldwide, and recent studies have shown that PALB2 also interacts with BRCA1. Here, we summarize the molecular functions and clinical phenotypes of this key DNA repair pathway component and discuss how its discovery has advanced our knowledge of both FA and adult cancer predisposition.
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PMID:PALB2/FANCN: recombining cancer and Fanconi anemia. 2085 16


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