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Wild-type BRCA1, but not mutated BRCA1, regulates the expression of the nuclear form of beta-catenin.

ABSTRACT: BRCA1 is an essential caretaker protein in the surveillance of DNA damage, is mutated in approximately 50% of all hereditary breast cancer cases, and its expression is frequently decreased in sporadic breast cancer. beta-Catenin is a multifunctional protein that forms adhesion complex with E-cadherins, alpha-catenin, and actin, and plays a central role in Wnt signaling through its nuclear translocation and activation of beta-catenin-responsive genes. Although significant progress has been made in understanding the Wnt/beta-catenin and BRCA1 signaling cascades, it is not known whether there is a link between beta-catenin and BRCA1. We observed that the expression of the active nuclear form of beta-catenin (also known as ABC, Ser37/Thr41-nonphosphorylated beta-catenin, dephosphorylated beta-catenin) was lower or absent in the nucleus in most BRCA1 familial breast cancer tissues (17 cases) compared with sporadic breast cancer (14 samples) and normal breast tissues. Wild-type-BRCA1, but not mutated BRCA1, interacted with beta-catenin and increased the levels of beta-catenin protein expression in vitro. Furthermore, H(2)O(2) induced the interaction of the nuclear form of beta-catenin with BRCA1. The active form of beta-catenin protein was downregulated upon exposure to H(2)O(2) in the nucleus of BRCA1-deficient HCC1937 breast cancer cells, whereas reconstitution of WT-BRCA1 in HCC1937 cells inhibited this downregulation. This study provides evidence of a novel interaction between BRCA1 and beta-catenin, and that loss of BRCA1 leads to impaired expression of the nuclear form of beta-catenin, which may contribute to the pathogenesis of breast cancer.

SUBMITTER: Li H

PROVIDER: S-EPMC2867250 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Wild-type BRCA1, but not mutated BRCA1, regulates the expression of the nuclear form of beta-catenin.

Li Huchun H Sekine Masayuki M Tung Nadine N Avraham Hava Karsenty HK

Molecular cancer research : MCR 20100309 3

BRCA1 is an essential caretaker protein in the surveillance of DNA damage, is mutated in approximately 50% of all hereditary breast cancer cases, and its expression is frequently decreased in sporadic breast cancer. beta-Catenin is a multifunctional protein that forms adhesion complex with E-cadherins, alpha-catenin, and actin, and plays a central role in Wnt signaling through its nuclear translocation and activation of beta-catenin-responsive genes. Although significant progress has been made i ...[more]

PMID: 20215423

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Project description:We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.SignificanceIn germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

Project description:Background: Breast cancer is a complex disease, encompassed by different clinically and molecularly stratified entities. In 2000, Perou and colleagues demonstrated that tumor phenotypic diversity correlates with differences in global gene expression patterns, which in turn reflect aspects of the biological behavior of the tumors. Gene expression profiling has distinguished sporadic breast tumor sub-classes with genetic, histopathological and clinical differences, however, little is known about the molecular classification of hereditary breast tumors. It has been recently suggested that most tumors arising in BRCA1 mutation carriers display a basal-like phenotype, with the percentages reported in different studies ranging from 44 to almost 100%. In the present study we used expression profiling to produce a molecular classification of BRCA1-associated breast tumors and applied an integrative approach to examine biological dependencies or differences. Methods and Findings: We used frozen tumor tissue from fourteen patients all of which harbored germline pathological mutations in BRCA1. Total RNA extraction, amplification and labeling with Cy5 were performed using standard protocols. Universal Human Reference RNA (Stratagene) was used as a reference and labeled with Cy3. Each pair of Cy3/Cy5 samples was hybridized onto the CNIO human OncoChip V2, which consists of a spotted microarray with 11,675 cDNA clones from the I.M.A.G.E. Consortium. Two channel ratios (Cy5/Cy3) for each spot were generated and quantified using GenePix Pro 5.1 (Axon Instruments, Inc., Union City, CA, USA). Data were normalized and filtered and multiple statistical analyses were performed. The data are deposited in the GEO database under the accession number GSE12350. A tissue microarray (TMA) containing an independent series of 15 BRCA1 tumors was used to validate some of the results obtained. We have described molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for Estrogen Receptor, ESR1. Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumors was mainly linked to cell proliferation-related processes and, therefore, regulated by the estrogen receptor, while the signature of ESR1-negative tumors was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFκB family. These signatures were then verified in an independent series of hereditary and sporadic breast tumors, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes appears to be a common feature of ER-negative sporadic and hereditary breast cancer and is associated with good prognosis. Interestingly, the ESR1-negative tumors were sub-stratified into two groups presenting light differences in the magnitude of the expression of immune response transcripts and REL/NFκB transcription factors, and this could be dependent on the type of germline alteration. In addition, analysis of the human protein-protein interaction network provides the wiring diagram of critical molecular associations in BRCA1 tumorigenesis and identifies close relationships between the different signatures. Conclusions: In summary, in the present study we have established the gene expression profiling of a series of BRCA1 tumors and found that there is a further degree of heterogeneity beyond the main classification by the expression of ESR1 and the presence or absence of a basal-like phenotype. We have identified specific signatures for ESR1-positive and ESR1-negative BRCA1 tumors, the latter characterized by the enrichment of immune response and cell cycle genes, and have found that slight differences in the level of expression of the immune response stratify the ESR1-negative BRCA1 tumors into two additional sub-groups (A and B) with possible prognostic differences. NFkB could be a major driver responsible for the levels of both immune response and apoptotic genes in this group of tumors, which could in turn be related to the type of germline mutation in BRCA1. This study reveals the molecular complexity of BRCA1 breast tumors, which are found to display similarities to sporadic tumors, and suggests possible prognostic implications. 14 samples (primary breast tumors containing a BRCA1 mutation) were hybridized to a cDNA microarray in order to investigate the possible heterogeneity within the BRCA1 group.

Dataset Information

Wild-type BRCA1, but not mutated BRCA1, regulates the expression of the nuclear form of beta-catenin.

Publications

Wild-type BRCA1, but not mutated BRCA1, regulates the expression of the nuclear form of beta-catenin.

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