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Project description:Carriers of germline BRCA1 mutations face a high risk of developing breast cancer; however, the mechanisms underlying this tumor predisposition are not completely understood. Here, using a newly developed genetically engineered mouse model for germline Brca1 heterozygosity that allows spatiotemporal control of full Brca1 inactivation, we demonstrate that the early tumor onset in a Brca1-heterozygous background cannot be fully explained by the conventional “two-hit” hypothesis. Specifically, when both Brca1-heterozygous and wild-type conditional mice are induced to Brca1 nullizygosity simultaneously, heterozygous mice develop tumors sooner, suggesting the existence of inherent tumor-promoting alterations in the Brca1-heterozygous state prior to tumor formation. Single-cell RNA-seq and ATAC-seq analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1-heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells, thereby pointing to an epigenetic priming mechanism for promoting early tumor onset in the Brca1-heterozygous background. Transcription factor analyses of the altered chromatin regions identify loss of ELF5 and gain of AP-1 binding sites in association with these epigenetically primed chromatin regions, and in vivo experiment reveals that Brca1-heterozygous mice are reliant on the AP-1 pathway for accelerated tumorigenesis. Finally, analysis of downstream target genes identifies Wnt10a as a candidate driver of early tumor onset, and functional experiments demonstrate that it activates the WNT pathway and is sufficient to substantially accelerate tumor formation. Taken together, these findings provide the first in vivo demonstration of a role of BRCA1 haploinsufficiency in accelerating tumor formation and implicate AP-1 and WNT10A as promoters of tumor formation in BRCA1-related breast cancer, advancing our understanding of the disease and informing potential strategies for therapeutic intervention.
2024-09-06 | GSE247453 | GEO
Project description:Carriers of germline BRCA1 mutations face a high risk of developing breast cancer; however, the mechanisms underlying this tumor predisposition are not completely understood. Here, using a newly developed genetically engineered mouse model for germline Brca1 heterozygosity that allows spatiotemporal control of full Brca1 inactivation, we demonstrate that the early tumor onset in a Brca1-heterozygous background cannot be fully explained by the conventional “two-hit” hypothesis. Specifically, when both Brca1-heterozygous and wild-type conditional mice are induced to Brca1 nullizygosity simultaneously, heterozygous mice develop tumors sooner, suggesting the existence of inherent tumor-promoting alterations in the Brca1-heterozygous state prior to tumor formation. Single-cell RNA-seq and ATAC-seq analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1-heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells, thereby pointing to an epigenetic priming mechanism for promoting early tumor onset in the Brca1-heterozygous background. Transcription factor analyses of the altered chromatin regions identify loss of ELF5 and gain of AP-1 binding sites in association with these epigenetically primed chromatin regions, and in vivo experiment reveals that Brca1-heterozygous mice are reliant on the AP-1 pathway for accelerated tumorigenesis. Finally, analysis of downstream target genes identifies Wnt10a as a candidate driver of early tumor onset, and functional experiments demonstrate that it activates the WNT pathway and is sufficient to substantially accelerate tumor formation. Taken together, these findings provide the first in vivo demonstration of a role of BRCA1 haploinsufficiency in accelerating tumor formation and implicate AP-1 and WNT10A as promoters of tumor formation in BRCA1-related breast cancer, advancing our understanding of the disease and informing potential strategies for therapeutic intervention.
2024-09-06 | GSE247451 | GEO
Project description:Slug (Snail2) plays critical roles in regulating the epithelial-mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled remain unclear. Herein we identify an unrecognized canonical Wnt/GSK3?/?-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3? and subsequently undergoes ?-Trcp1-dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3? kinase activity is inhibited, nuclear Slug levels increase, and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels, and reduced expression of the tumor suppressor Breast Cancer 1, Early Onset (BRCA1), further studies demonstrate that Slug-as well as Snail-directly represses BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients. Together, these findings establish unique functional links between canonical Wnt signaling, Slug expression, EMT, and BRCA1 regulation.
| S-EPMC3478591 | biostudies-literature
Project description:Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-?, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.
| S-EPMC7578789 | biostudies-literature
Project description:Eighty-six women fulfilling specific selection criteria were studied for germline mutations in two breast cancer susceptibility genes, BRCA1 and BRCA2, using the protein truncation test (PTT). Nine germline mutations were identified, six in BRCA1 and three in BRCA2. Of the six BRCA1 mutations, three have previously been described and three are new, and for BRCA2, one is a new mutation and the other two appear to occur at a site that has been described several times. Four kindreds were breast cancer families, one a breast/ovarian cancer family, and the sixth an ovarian cancer family. The three kindreds with BRCA2 mutations were classified as one breast/ovarian cancer family, one breast cancer family, and one family which harboured one early onset breast cancer patient and two melanoma patients. The mutations in BRCA1 were either insertions, deletions, or transitions which all resulted in a premature stop codon. Mutations in BRCA2 were all frameshift mutations as a result of either 2 or 4 bp deletions. Two BRCA2 mutations were identical, suggesting a Swiss founder effect which was confirmed by haplotype sharing. The 10% mutation detection rate is compatible with the relaxed criteria used for patient selection. Considering the relative ease with which coding sequences can be screened by PTT, this assay is useful as a first screen for BRCA1 and BRCA2 mutations.
| S-EPMC1051149 | biostudies-other
Project description:Women carrying germline mutations in BRCA1 are at a substantially elevated risk of breast cancer and their tumors typically have distinctive morphologic features. We hypothesized that constitutional methylation of the BRCA1 promoter region could give rise to such breast cancers in women. We selected 255 women diagnosed with breast cancer before the age of 40 years for whom BRCA1 germline mutations had not been identified. Of them, 52 had five or more of nine BRCA1 mutation-associated morphologic features (group 1), 39 had four (group 2), and 164 had three or less (group 3). The prevalence of detectable BRCA1 promoter methylation in peripheral blood DNA decreased from 31% to 10% to 5% across groups 1-3, respectively (P = 0.000002), and was significantly greater than the 4% frequency in unaffected controls (P = 0.004). Peripheral blood methylation was associated with a 3.5-fold (95% CI, 1.4-10.5) increased risk of having early onset breast cancer. Methylation was consistently mosaic in the peripheral blood where the estimated allelic frequency of BRCA1 promoter methylation ranged from 0.1% to 17%. Group 1 women, but not group 3 women, with detectable methylation of peripheral blood DNA had high levels of BRCA1 promoter methylation of their tumor DNA, indicating that constitutional BRCA1 methylation strongly predisposes toward the development of BRCA1 methylated tumors that then have features resembling BRCA1 mutated tumors. Screening peripheral blood for BRCA1 promoter methylation might thus predict early-onset breast cancers. This raises the possibility of chemoprevention or other intervention to diminish the risk of developing breast cancer in these women.
| S-EPMC4030007 | biostudies-literature
Project description:Aberrant activation of ?-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the ?-catenin signaling pathway over the past three decades, attempts to develop therapies targeting ?-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing ?-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2KI), which exhibits aberrant ?-catenin nuclear signaling, ?-catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both ?-catenin alleles in the ErbB2KI model had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (?-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2KI basal tumor model, modulation of ?-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear ?-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer.
| S-EPMC5293039 | biostudies-literature
Project description:The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in approximately 50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10-2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06-2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04-3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.
| S-EPMC2833356 | biostudies-literature
Project description:Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression.
| S-EPMC3100488 | biostudies-literature
Project description:Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations.
| S-EPMC5949367 | biostudies-literature