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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE28712 | GEO | 2012/05/30

SECONDARY ACCESSION(S): PRJNA139007

REPOSITORIES: GEO

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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

Lunatic fringe deficiency cooperates with the Met/Caveolin amplicon to induce basal-like breast cancer

2012-05-30 | GSE35855 | GEO

Lunatic fringe deficiency cooperates with the Met/Caveolin amplicon to induce basal-like breast cancer

Project description:Mammary specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling. Tumor DNAs from Lfngflox/flox; MMTV-Cre conditional mutant mice are being compared to control DNAs from the same animals in order to identify common alterations associated with tumor progression

2012-05-29 | E-GEOD-35855 | biostudies-arrayexpress

Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer

Project description:Elevated Met receptor tyrosine kinase (RTK) expression correlates with poor outcome in breast cancer, yet a causal role for Met in the development of breast cancer has not been directly established. To examine this question, we generated a transgenic mouse model that targets expression of an oncogenic Met receptor (MetMut) to the mammary epithelium. We show that MetMut induces mammary tumors with a variety of histopathologies that exhibit gene expression profiles sharing similarities with human basal and luminal breast tumor subtypes. Among all breast cancers, we further demonstrate that the Met receptor is primarily overexpressed in human basal and HER2 positive breast cancers, and that a Met associated gene expression signature identifies patients with poor prognosis. Keywords: Met, mammary, poor outcome, EMT, basal breast cancer

2009-03-30 | GSE10450 | GEO

Affymetrix SNP array data for Trp53-null mammary tumors developed in 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, 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.

2016-12-20 | GSE77497 | GEO

Transcription profiling of a mouse transgenic that targets expression of an oncogenic Met receptor reveals Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer

Project description:Elevated Met receptor tyrosine kinase (RTK) expression correlates with poor outcome in breast cancer, yet a causal role for Met in the development of breast cancer has not been directly established. To examine this question, we generated a transgenic mouse model that targets expression of an oncogenic Met receptor (MetMut) to the mammary epithelium. We show that MetMut induces mammary tumors with a variety of histopathologies that exhibit gene expression profiles sharing similarities with human basal and luminal breast tumor subtypes. Among all breast cancers, we further demonstrate that the Met receptor is primarily overexpressed in human basal and HER2 positive breast cancers, and that a Met associated gene expression signature identifies patients with poor prognosis. Experiment Overall Design: Common reference design. 26 samples (including 20 normal tissue and 32 tumor tissue samples) replicated twice as dye swaps, generating a total of 52 arrays.

2009-04-03 | E-GEOD-10450 | biostudies-arrayexpress

Identification of pro-metastatic pathways and molecules in mouse models with reduced expression or signaling of the insulin-like growth factor type 1 receptor

Project description:We performed single-cell RNA sequencing of multiple IGF-1R loss-of function mouse mammary tumor models to uncover how IGF-1R signaling regulates intrinsic epithelial cell signaling to suppress metastasis. We identify key pathways necessary for promoting metastasis, determined IGF-1R is required to maintain a metastatic suppressive tumor microenvironment and demonstrate that attenuated epithelial IGF-1R signaling in the MMTV-Wnt1 mouse tumor model is sufficient for metastatic invasion. We further show that adherence between luminal and basal tumor cells is necessary for tumor growth at the secondary site and that reduced IGF-1R signaling in tumor epithelial cells inhibits secondary tumor epithelial cell growth due to dysregulated E-cadherin and P-cadherin and loss of cell-cell adhesion.

2022-11-21 | GSE182236 | GEO

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.

2016-12-20 | GSE77496 | GEO

Transcriptional profiling of MMTV-tTA/TOP-ICN1 tumor derived cell lines comparing untreated (ICN1-On) cells to 24-hour doxcycline treated (ICN1-Off) samples

Project description:NOTCH activation has been recently implicated in human basal-like breast cancers associated with a poor prognosis. To address the role of Notch1 in mammary transformation and mammary tumor initiating cell activity, we developed a doxycycline-regulated model of Notch1-mediated mammary transformation. These mice develop mammary adenocarcinomas that express cytokeratin (CK) 8/18 and contain rare cells that also express keratin 14. In vivo limiting dilution analyses reveal that these mammary tumors exhibit functional heterogeneity and harbor a rare (1/2978) mammary tumor initiating cell population. Using this dox-regulated Notch1 mammary tumor model, we demonstrate that Notch1 inhibition results in mammary tumor regression in vivo and prevents disease recurrence in 4 of 6 tumors tested. Consistent with the in vivo data, Notch1 inhibition reduces mammary tumorsphere forming activity in vitro. Using doxycycline-responsive tumor derived cell lines, we also identify the embryonic stem cell transcription factor Nanog as a novel Notch1-regulated gene in mammospheres. These data indicate that Notch1 contributes to mammary tumor initiating activity and raises the possibility that NOTCH therapeutics may have efficacy in human basal-like breast cancers associated with NOTCH activation.

2011-12-05 | GSE34146 | GEO

Rnf8 loss promotes breast carcinogenesis

Project description:Coordination of signaling pathways is essential for tissue homeostasis and for preventing cancer development. Here, we show that the E3 ligase Rnf8, an important component of the DNA double-strand break (DSB) signaling, is critical for cell-fate commitment of the mammary epithelial progenitors. Furthermore, we provide evidence that deficiency of Rnf8 predisposes mouse models for mammary tumorigenesis while low expression levels in breast cancer associates with poor patient prognosis. RNF8 mediates these novel functions through ubiquitylation and degradation of the activated form of NOTCH1, and thereby fine-tuning of NOTCH signaling. Accordingly, RNF8 level negatively correlates with the expression of NOTCH targets in mouse mammary and human breast tumors. Consistent with these findings, Rnf8-deficient mammary tumors are highly sensitive to pharmacological inhibition of NOTCH. Therefore, RNF8 inhibits breast cancer on two fronts, maintaining genomic stability through DSB signaling and regulating growth and differentiation through inhibition of the NOTCH pathway.

2017-01-01 | GSE76075 | GEO

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