Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA358691 | ENA |
REPOSITORIES: ENA
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Project description:Rank signaling regulates mammary gland development and epithelial cell differentiation. Rank receptor is expressed by mammary basal and luminal populations, but, unlike luminal Rank, the contribution of basal Rank signaling to MG homeostasis remains poorly studied. We have combined timely regulated basal specific Rank expression with lineage tracing models and unveiled that basal Rank signaling controls basal cell identity in postnatal mammary glands. Ectopic basal Rank disrupts basal but also luminal cell identity, resulting in aberrant luminal-like differentiation of basal cells and impaired lactogenesis. Mechanistically, overactivation of basal Rank signaling leads to basal cell lineage infidelity, illustrated by the appearance of premalignant lesions composed by a basal-derived hybrid population with alveolar features which ultimately generates basal and luminal breast adenocarcinomas. Proteomic, transcriptomic and chromatin analyses support that the loss of tumor suppressive epigenetic regulators driven by basal Rank contributes to epithelial cell dedifferentiation and tumorigenesis. The basal Rank signature generated associates to poor prognosis particularly in human adenocarcinomas of the luminal subtype stressing the clinical relevance of our findings. Interestingly, our results reinforce the idea that luminal breast tumors might originate from basal cells that have suffered a luminal-like aberrant dedifferentiation triggered by Rank signaling.
2026-02-02 | PXD054102 | Pride
Project description:Rank signaling regulates mammary gland development and epithelial cell differentiation. Rank receptor is expressed by mammary basal and luminal populations, but unlike that of luminal, the contribution of basal Rank signaling to mammary gland homeostasis remains poorly studied. Combining timely-regulated, basal-specific Rank expression with lineage tracing strategies we unveiled that Rank signaling controls basal cell identity in postnatal mammary glands. Enhanced basal Rank disrupts basal and luminal cell identity, resulting in aberrant luminal-like differentiation of basal cells, defective lactation and the appearance of premalignant lesions composed of a basal-derived hybrid population with luminal/alveolar features, which ultimately generates basal and luminal breast adenocarcinomas. Mechanistically, phospho-proteomic, transcriptomic and chromatin analyses support that basal Rank activation triggers the loss of tumor suppressive epigenetic regulators, leading to chromatin remodeling, disruption of basal identity and tumorigenesis. We uncover a basal Rank gene signature that can be predictive of progression from in situ to invasive adenocarcinomas and associates with poor prognosis in breast cancer patients, particularly in those diagnosed with luminal adenocarcinomas, underlining the clinical relevance of our findings. Our results reinforce the idea that basal lineage infidelity triggered by Rank signaling contribute to generation from pre-invasive lesions and transition to invasive breast cancer.
2026-02-02 | PXD058134 | Pride
Project description:p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression. We have investigated how transcriptional regulation contributes to the tumor suppressor effect of p38α, by comparing whole-genome expression profiles of wild-type (WT) and p38α- deficient (p38α-/-) mouse embryo fibroblasts (MEFs) expressing oncogenic H-RasG12V
2011-11-23 | E-GEOD-26762 | biostudies-arrayexpress
Project description:GATA-3 maintains luminal cell differentiation in the mammary gland and in breast cancer
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Project description:Rank signaling regulates mammary gland development and epithelial cell differentiation. Rank receptor is expressed by mammary basal and luminal populations, but, unlike luminal Rank, the contribution of basal Rank signaling to MG homeostasis remains poorly studied. We have combined timely regulated basal specific Rank expression with lineage tracing models and unveiled that basal Rank signaling controls basal cell identity in postnatal mammary glands. Ectopic basal Rank disrupts basal but also luminal cell identity, resulting in aberrant luminal-like differentiation of basal cells and impaired lactogenesis. Mechanistically, overactivation of basal Rank signaling leads to basal cell lineage infidelity, illustrated by the appearance of premalignant lesions composed by a basal-derived hybrid population with alveolar features which ultimately generates basal and luminal breast adenocarcinomas. Proteomic, transcriptomic and chromatin analyses support that the loss of tumor suppressive epigenetic regulators driven by basal Rank contributes to epithelial cell dedifferentiation and tumorigenesis. The basal Rank signature generated associates to poor prognosis particularly in human adenocarcinomas of the luminal subtype stressing the clinical relevance of our findings. Interestingly, our results reinforce the idea that luminal breast tumors might originate from basal cells that have suffered a luminal-like aberrant dedifferentiation triggered by Rank signaling
2026-01-16 | GSE272968 | GEO
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we provide evidence that the protein kinase p38a is required for the differentiation of luminal progenitor cells through modulation of the transcription factors Runx1 and Foxa1. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38a downregulation in mammary epithelial cells reduces tumorigenesis, which correlates with reduced numbers of tumor-initiating cells. Our results identify p38a as a key regulator of luminal progenitor cell fate that facilitates mammary tumor formation.
2017-12-28 | GSE92877 | GEO
Project description:Expression and functional validation of new p38α transcriptional targets in tumorigenesis
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Project description:PTEN-deficiency in luminal MMTV-ErbB-2 mouse model results in dramatic acceleration in mammary tumorigenesis/metastasis
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