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Affymetrix SNP array data for Trp53-null mammary tumors developed in a mouse model with a K8+ luminal cell origin

ABSTRACT: Mammary epithelium is hierarchically organized, with multipotent basal mammary stem cells (MaSCs) producing both luminal and basal cells during development or upon transplantation. Recent studies suggested that most breast cancers, including Basal-Like breast cancer (BLBC), might originate from luminal cells, and oncogenic events, such as ectopic expression of PIK3CA(H1047R), could induce multipotency in committed luminal cells. p53 is the most commonly mutated gene in human breast cancer; in particular, its inactivating mutations are found in most BLBCs, raising a question as to whether p53-loss plays a key role in acquisition of multipotent MaSC-like properties by luminal cells. By in situ lineage-tracing, we found that induced loss of p53 in Keratin 8 (K8)+ luminal cells led to their clonal expansion, due to increased cell cycle activity and attenuated apoptosis control, but did not directly affect their luminal identity. All induced mice eventually developed either Claudin-Low mammary tumors with 9qA1 (Yap1) amplification or Basal-Like tumors with 6qA1-A2 (Met) amplification. These data suggest that although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumors with loss of luminal identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE77497 | GEO | 2016/12/20

SECONDARY ACCESSION(S): PRJNA310636

REPOSITORIES: GEO

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Microarray expression profiling data for Trp53-null mammary epithelial cells and tumors from a mouse model with a K8+ luminal cell origin

Project description:Mammary epithelium is hierarchically organized, with multipotent basal mammary stem cells (MaSCs) producing both luminal and basal cells during development or upon transplantation. Recent studies suggested that most breast cancers might originate from luminal cells, and oncogenic events, such as ectopic expression of PIK3CAH1047R, could induce multipotency in committed luminal cells. p53 is the most commonly mutated gene in human breast cancer; in particular, its inactivating mutations are found in most triple-negative breast cancers, raising a question as to whether p53-loss plays a key role in acquisition of MaSC-like properties by luminal cells. By in situ lineage tracing, we found that induced loss of p53 in Keratin 8 (K8)+ luminal cells led to their clonal expansion, in part due to increased proliferation, but did not directly affect their luminal identity. Expansion of luminal cells, in particular oestrogen receptor-positive luminal cells, was observed 3-4 weeks after induced p53-loss, which was accompanied by increased expression of cell cycle genes and downregulation of genes related to immune microenvironment, p53 downstream pathway and apoptosis control. All induced mice eventually developed mammary tumours with 9qA1 (Yap1) amplification and/or 6qA2 (Met) amplification. The resulting tumours exhibited a MaSC-like expression signature and most closely resembled Claudin-Low breast cancer. Overall, these data suggest that although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumours with loss of luminal identity. Our data also suggest that Claudin-Low breast cancer can originate from luminal cells, possibly upon transition through a basal-like state.

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Rb deletion in mammary stem/progenitor epithelium induces tumors with features of luminal-B or basal-like breast cancer

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2010-07-06 | E-GEOD-14457 | biostudies-arrayexpress

Rb deletion in mammary stem/progenitor epithelium induces tumors with features of luminal-B or basal-like breast cancer

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Expression data from sorted control and Pygo2-null mouse mammary stem/basal cells

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Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-Like Breast Cancer

Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples

2012-05-29 | E-GEOD-28712 | biostudies-arrayexpress

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.

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Histone methylation profiles of prospectively isolated mammary epithelial subpopulations

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Single cell RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells and tumor 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 at different time points after the intraductal injection, as well as mammary tumors developed in this model, by single cell expression analysis.

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Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-Like Breast Cancer

2012-05-30 | GSE28712 | 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

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