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Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer (scRNA-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE247451 | GEO | 2024/09/06

REPOSITORIES: GEO

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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.

Project description:In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar pathophysiological mechanisms. Grouping into molecularly homogeneous subsets may therefore be of potential value for further genetic analysis in order to identify new high penetrance breast cancer genes. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. By analyzing a collection of 70 breast tumor biopsies from 58 families, we show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Our finding indicates involvement of hereditary factors in these families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. This is the first study to provide a biological link between breast cancers from family members of high risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to identify new high penetrance susceptibility genes. Gene expression profiling of 253 breast tumor samples. Breast tumor tissue from 125 patients with germline mutations in BRCA1 (n = 33) or BRCA2 (n = 22) or with no detectable germline mutation in BRCA1 or BRCA2 (n = 70) were included in the study. Serving as a representative control group, primary breast tumor samples (n = 128) were randomly selected among available samples originating from the same department and time period as for the hereditary samples. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform.

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Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer (scRNA-Seq)

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