Rank pathway activation attenuates mammary tumorigenesis by inducing senescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139675 | GEO | 2022/02/24
REPOSITORIES: GEO
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Project description:Rank pathway activation attenuates mammary tumorigenesis by inducing senescence
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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 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: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 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: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 | GSE272902 | GEO
Project description:Disruption of basal cell identity by Rank signaling drives mammary tumorigenesis
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Project description:Disruption of basal cell identity by Rank signaling drives mammary tumorigenesis
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Project description:The purpose of this study was to elucidate the molecular changes of the mammary epithelium induced by luminal cell specific RANK deletion. We have characterized the phenotypic consequences of RANK deletion in the luminal lineage of the mammary epithelium, and uncovered that Rank KO luminal cells have reduced long term renewal following sucessive pregnancies. Lineage tracing analysis has demonstrated that during pregnancy 2, Rank deleted luminal cells are repleace by a wt luminal cell population, derived from the basal epithelium. We therefore decided to perform RNA seq in resting mammary glands from virgin and parous (following pregnancy one) females, cells were FACS sorted based on the traditional markers CD24 and CD49f and in the case of luminal cells GFP (recombined cells). We have isolated luminal cells to identify the molecular pathways involved in reduced long term renewal oberved in the parous context; basal cells were isolated to adress the putative mechanims regulated the bipotency observed during second pregnancy
2023-09-01 | GSE199746 | GEO
Project description:The transcriptional profile of WapCre;Rank;Brca1;p53 and WapCre;Brca1;p53 mouse primary mammary tumor cells was determined by mRNA sequencing and uncovered differences in their molecular signatures including genes involved in oncogenesis, basic metabolism, RNA metabolism, or the regulation of mammary stem cells.
2017-02-12 | GSE71362 | GEO
Project description:Transcriptional profile of either RANK+/+ or RANK-/- MMTV-PyMT late carcinomas, orthotopically injected in syngeneic RANK+/+ mice. Once host mice developed tumors, CD45- tumor cells were sorted by flow cytometry in order to compare changes on tumor gene expression caused by the absence of RANK protein.
2020-10-06 | GSE119464 | GEO