Dataset Information

PMEPA1 mediates resistance to mTOR inhibitors in triple-negative breast cancer via dual modulation of TGF-β signaling and PI3K/AKT activation

ABSTRACT: Acquired resistance to mammalian target of rapamycin inhibitors (mTORi) severely limits their clinical efficacy in triple-negative breast cancer (TNBC), a subtype devoid of targeted therapeutic options. To model acquired resistance, we established two mTORi-resistant TNBC cell lines, MDA-MB-231/DREVE and MDA-MB-231/DRRIDA, through chronic exposure to everolimus and ridaforolimus, respectively. These resistant cells exhibited sustained mTOR signaling, evasion of G1 arrest, enhanced migratory potential, and anchorage-independent growth. Transcriptome profiling by whole RNA Sequencing coupled with GSEA analyses revealed convergent activation of the PI3K/AKT axis and upregulation of TGF-β and KRAS signaling, alongside suppression of IL-2-mediated responses. Integrative analysis identified PMEPA1, a known modulator of TGF-β signaling, as a key driver of resistance. PMEPA1 expression was elevated in resistant cells and correlated with poor survival in TNBC patients. We demonstrated that PMEPA1 confers resistance to mTORi by suppressing canonical SMAD signaling while promoting activation of the PI3K/AKT/mTOR pathway through PTEN downregulation. Targeted silencing of PMEPA1 restored drug sensitivity, reversed epithelial–mesenchymal transition (EMT), and impaired stem-like properties. Pharmacological inhibition of upstream TGF-β signaling with galunisertib downregulated PMEPA1 and synergistically restored mTORi sensitivity in in-vitro and xenograft models, leading to significant tumor regression. Histological analysis confirmed reduced proliferation, angiogenesis, and PMEPA1 expression while necrotic foci increased in combination treated tumors. These findings establish PMEPA1 as a dual modulator of canonical and non-canonical TGF-β signaling, and a critical mediator of mTORi resistance in TNBC. Targeting the TGF-β/PMEPA1 axis represents a promising strategy to overcome resistance and improve outcomes in patients with mTORi-refractory TNBC

ORGANISM(S): Homo sapiens

PROVIDER: GSE309057 | GEO | 2026/03/06

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Patients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated. Methods: IFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting. Results: Here, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition (EMT)-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling. Conclusions: Our findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor (OSMR) would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies.

Dataset Information

PMEPA1 mediates resistance to mTOR inhibitors in triple-negative breast cancer via dual modulation of TGF-β signaling and PI3K/AKT activation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets