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ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling

ABSTRACT: ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling

PROVIDER: PRJNA205866 | ENA |

REPOSITORIES: ENA

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ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.

Project description:Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

| S-EPMC4183725 | biostudies-literature

ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-08-19 | E-GEOD-47493 | biostudies-arrayexpress

ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-08-19 | GSE47493 | GEO

Disrupted transcripitonal network in ΔNp63 AEC tissue model

Project description:This SuperSeries is composed of the following subset Series: GSE33495: Disrupted transcripitonal network in ΔNp63 AEC tissue model [gene expression] GSE33571: Disrupted transcriptional network in ΔNp63 AEC tissue model [ChIP-Seq] Refer to individual Series

2012-06-17 | E-GEOD-33572 | biostudies-arrayexpress

Noncanonical Wnt/Ror2 Signaling Regulates Basal Cell Fidelity and Branching Morphogenesis in the Mammary Gland.

Project description:The mammary gland epithelium relies on a delicate balance between basal and luminal cell lineages to maintain tissue homeostasis and enable proper development. While the role of canonical Wnt signaling in mammary biology is well-established, the contribution of noncanonical Wnt signaling to lineage identity has remained unclear. Noncanonical Wnt pathways are primarily associated with morphogenesis, cytoskeletal regulation, and cell migration, but whether they are required for maintaining epithelial cell fate remains largely unexplored. Here, we demonstrate that the noncanonical Wnt receptor Ror2 is expressed in both basal and luminal lineages, yet selectively maintained in basal cells throughout development, suggesting a lineage-specific function. Using a p63CreERT2/+ lineage-specific mouse model, we show that Ror2 deletion in basal epithelial cells enhances secondary and tertiary branching while driving a basal-to-luminal fate transition, marked by downregulation of basal markers (K14, K5) and upregulation of luminal markers (K8, K18, ERα). Mechanistically, Ror2 loss disrupts RhoA-ROCK1-YAP1 signaling, leading to cytoskeletal reorganization, chromatin remodeling, and increased accessibility at luminal regulatory loci. Notably, ROCK1 inhibition phenocopies Ror2 loss, reinforcing the critical role of the RhoA-ROCK1 axis in basal cell maintenance. These findings provide direct genetic and mechanistic evidence that noncanonical Wnt signaling is essential for maintaining basal lineage fidelity, offering new insights into the mechanisms regulating epithelial plasticity. Given the fundamental importance of lineage stability in epithelial homeostasis, our results suggest that disruptions in Wnt/Ror2 signaling may contribute to aberrant fate transitions relevant to breast cancer progression.

| S-EPMC11888327 | biostudies-literature

ΔNp63 controls stemness and inflammation in the adult epidermis

Project description:The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is barely investigated. Here we show that acute genetic ablation of ΔNp63, the main p63 isoform, in the adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in ΔNp63-ablated keratinocytes. Intriguingly, ΔNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This was not associated with active cell death mechanisms, but rather with reduced stemness and self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, was largely impaired in the ablated skin. We found that the Wnt signaling pathway (Wnt5a, Wnt10a, Fzd6, Fzd10) and Col17a1 are the likely ΔNp63 effectors responsible for keratinocyte proliferation and stemness, while AP1 factors are responsible for excessive differentiation, and Il-1a, Il-18, Il-24 and Il-36γ for the suppression of inflammation. These data implicate ΔNp63 as a critical node that coordinates balanced epidermal homeostasis and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.

2023-03-31 | GSE213528 | GEO

Transcriptome analyses of luminal-derived basal cells induced by hormones in the mammary gland

Project description:We have used RNA-seq to examine RNA differential expression among three populations, normal basal cells, luminal-derived basal cells (LdBCs) and normal luminal cells.

2019-12-31 | GSE109543 | GEO

Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis.

Project description:Establishing apical-basal epithelial cell polarity is fundamental for mammary gland duct morphogenesis during mammalian development. While the focal adhesion adapter protein paxillin is a well-characterized regulator of mesenchymal cell adhesion signaling, F-actin cytoskeleton remodeling and single cell migration, its role in epithelial tissue organization and mammary gland morphogenesis in vivo has not been investigated. Here, using a newly developed paxillin conditional knockout mouse model with targeted ablation in the mammary epithelium, in combination with ex vivo three-dimensional organoid and acini cultures, we identify new roles for paxillin in the establishment of apical-basal epithelial cell polarity and lumen formation, as well as mammary gland duct diameter and branching. Paxillin is shown to be required for the integrity and apical positioning of the Golgi network, Par complex and the Rab11/MyoVb trafficking machinery. Paxillin depletion also resulted in reduced levels of apical acetylated microtubules, and rescue experiments with the HDAC6 inhibitor tubacin highlight the central role for paxillin-dependent regulation of HDAC6 activity and associated microtubule acetylation in controlling epithelial cell apical-basal polarity and tissue branching morphogenesis.

| S-EPMC6526716 | biostudies-literature

ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes

Project description:ΔNp63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function, maintaining the integrity of stratified epithelial cells and committing epidermal cells to the differentiation program. To this end, ΔNp63 exploits several direct mechanisms. Here, we elucidated a novel mechanism whereby ΔNp63 efficiently sustains the expression of epidermal differentiation genes. We show that ΔNp63 interacts with Senataxin (SETX), an RNA/DNA helicase able to resolve the R-loop intermediates over the GC-rich termination sites of coding genes. Notably, we found that SETX and ΔNp63 co-regulate a subset of genes involved in the early step of the keratinocyte differentiation program. At the molecular level, SETX physically binds the p63 DNA binding motifs present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3’ ends and thus promoting efficient transcriptional termination and gene expression. Remarkably, SETX loss affects the activation of the proper epidermal differentiation program in vitro and impacts epidermal layer stratification in organotypic human skin. Furthermore, we found that SETX is mutated or downmodulated in SCC and SETX gene mutation is a negative prognostic factor for cutaneous SCC patient survival. Collectively, our results unveil SETX as a novel molecular player of skin homeostasis, potentially involved in hyperproliferative skin disorders.

2022-01-10 | GSE193205 | GEO

Transcriptome analysis of luminal and basal cell subpopulations in the lactating versus pregnant mammary gland

Project description:To identify genes specifically expressed in lactating mammary glands, the gene expression profiles of luminal and basal cells from different developmental stages were compared. Comparison of gene expression in luminal and basal cells harvested from the mammary glands of virgin, 18.5 day pregnant and 2 day lactating mice (2 mice per stage).

2015-01-19 | E-GEOD-60450 | biostudies-arrayexpress

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