Cholesterol pathway inhibition induces TGFβ signaling to promote basal differentiation in pancreatic cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA657051 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12450154_1.fastq.gz | Fastqsanger.gz | |||
| SRR12450154_2.fastq.gz | Fastqsanger.gz | |||
| SRR12450155_1.fastq.gz | Fastqsanger.gz | |||
| SRR12450155_2.fastq.gz | Fastqsanger.gz | |||
| SRR12450156_1.fastq.gz | Fastqsanger.gz |
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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
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