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Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

ABSTRACT: Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

PROVIDER: PRJNA824513 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR32163135_1.fastq.gz	Fastqsanger.gz
	SRR32163135_2.fastq.gz	Fastqsanger.gz
	SRR32163136_1.fastq.gz	Fastqsanger.gz
	SRR32163136_2.fastq.gz	Fastqsanger.gz

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Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

Project description:Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

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Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

Project description:Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

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Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

Project description:In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.

2025-04-23 | GSE288315 | GEO

Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

2025-04-23 | GSE200444 | GEO

Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

Project description:Defects in double-strand repair mechanisms - both through germline or somatic inactivation of repair genes - is a hallmark of basal-like breast cancers. In this genetically-unstable context, a recurrent major shift in cell identity occurs within the mammary epithelium. Basal-like BRCA1 tumors have indeed been proposed to originate from luminal progenitor cells yet tumor-initiating events remain poorly understood. Here, we map the state transitions leading luminal progenitors to tumor formation, using a mouse model launching tumorigenesis in multiple LP cells. We identify a population of cycling p16-expressing cells, emerging from the luminal progenitor compartment, undergoing partial epithelial-to-mesenchymal transition and losing luminal identity. Pseudo-temporal analyses position these cells as a transitory state between aberrant Brca1-deficient luminal progenitors and growing tumor cells. Concomitant to p16 activation, we show that LP cells undergo an epigenomic crisis attested by the general re-organization of their heterochromatin. They accumulate multiple H3K27me3 micro-foci - reminiscent of the formation of senescence-associated heterochromatin foci (SAHFs) - and lose their inactive X (Xi). Both p16 activation and heterochromatin reorganization are hallmarks of human basal-like breast tumors, we propose that these events occur during initial LP transformation and are scars of an initial transitory senescent-like state.

2025-04-23 | GSE198337 | GEO

Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors

Project description:One of the major hurdles for the early detection of cancer is our poor understanding of tumour initiating events. Historically, cancer research has focused on histological and molecular characterisation of established tumours, which has led to the identification of hundreds of putative driver mutations. It is currently unclear how these genetic aberrations impact the cell state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) for example has been shown to arise from luminal progenitor cells1,2 yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that the perturbation of Brca1/p53 in luminal progenitors induces an aberrant alveolar differentiation pre-malignancy. Unlike alveolar differentiation occurring during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Our experimental approach has allowed us to further identify responses in the stromal and immune cell compartments during the early steps of tumourigenesis. Based on our data we propose a model where transcriptional and epigenetic changes driven by Brca1/p53 inadvertently promote a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell of origin and offering a potential explanation for the tissue specificity of BRCA1 tumours. Moving forward, the phenotype identified herein should be evaluated as a target for early detection and treatment of TNBC.

2021-02-02 | E-MTAB-10043 | biostudies-arrayexpress

GATA3 truncation mutants alter EMT related gene expression via partial motif recognition in luminal breast cancer cell

Project description:GATA3 is one of the most frequently mutated genes in breast cancer. The roles of GATA3 mutations remain elusive. In this study, we characterized newly established luminal breast cancer cell lines that stably express different GATA3 patient-derived mutants (Splice site deletion, C321 frame-shift, and A333 frame-shift mutants). The expression of these mutants lead to altered expression of EMT related genes as well as redistribution of GATA3.

2022-01-15 | GSE190381 | GEO

Microarray expression profiling data for Trp53/Brca1-null mammary tumors derived from K8+ luminal cells

Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC.

2019-06-27 | GSE114787 | GEO

RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells with a K8+ luminal origin

Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre one month after the intraductal injection.

2019-06-27 | GSE126761 | GEO

Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors

Project description:One of the major hurdles for the early detection of cancer is our poor understanding of tumour initiating events. Historically, cancer research has focused on histological and molecular characterisation of established tumours, which has led to the identification of hundreds of putative driver mutations. It is currently unclear how these genetic aberrations impact the cell state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) for example has been shown to arise from luminal progenitor cells yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that the perturbation of Brca1/p53 in luminal progenitors induces an aberrant alveolar differentiation pre-malignancy. Unlike alveolar differentiation occurring during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Our experimental approach has allowed us to further identify responses in the stromal and immune cell compartments during the early steps of tumourigenesis. The data in this repository contains the human bulk RNA-sequencing that was presented as part of this study.

2021-02-02 | E-MTAB-10046 | biostudies-arrayexpress

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