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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:Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer
| PRJNA1037576 | ENA
Project description:Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer (ATAC-Seq)
| PRJNA1037580 | ENA
Project description:Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer (scRNA-Seq)
| PRJNA1037578 | ENA
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/GSK3β/β-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3β and subsequently undergoes β-Trcp1-dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3β 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-γ, 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:According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year-span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran-Mantel-Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6-6.6) and 2.5% (95% CI 1.4-3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding-together with a relatively high VEO-BC risk for women with BRCAm-advocates for MRI breast screening from age 25 regardless of family history.
| S-EPMC8305427 | biostudies-literature
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