Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

ABSTRACT: Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS as well as regulators of EMT play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE157333 | GEO | 2021/05/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [human]

Project description:The newly identified claudin-low subtype of cancer is believed to represent the most primitive breast malignancies, having arisen from transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this hypothesis, we show both in vitro and in vivo that transcription factors inducing epithelial-mesenchymal transition can drive the development of claudin-low tumors from differentiated mammary epithelial cells, by playing a dual role in cell transformation and dedifferentiation. Human mammary epithelial cells (HMEC) were sequentially immortalized by hTert (HMEC-hTert), transduced with Twist1 or Zeb2 or Zeb1 and then with H-RasG12V. The gene expression profiles of the resulting HMEC-hTert-Twist1+Ras, HMEC-hTert-Zeb1+Ras and HMEC-hTert-Zeb2+Ras cell lines were defined. HMEC-hTert-Twist1+Ras and HMEC-hTert-Zeb2+Ras cell lines were additionally cultured in presence of TGFM-CM-^C? and their gene expression profiles were determined. The parental HMEC-hTert, the luminal MCF7 and the basal B MDMB157cell lines were used as controls.

2012-07-23 | E-GEOD-32727 | biostudies-arrayexpress

Isolation of subtype-specific N-Ras responsive genes in basal-like breast cancer cells

Project description:To identify the the N-Ras-controlled genes in basal-like cells, we used shRNA to repress N-RAS in basal-like SUM102PT, SUM149PT and claudin-low SUM159PT cells. We seek the genes regulated only in basal-like, but not in claudin-low cells, to isolate the genes controlled by N-Ras in a breast cancer subtype-specific fashion. We also overexpressed oncogenic form N-Ras(G12D) in these cells in order to compare the genes regulated by wild-type and oncogenic N-Ras. The shRNA silencing and overexpression were conducted by lentiviral infection in the cells, with non-silencing shRNA-infected cells as the controls. The infected cells were then selected in antibiotics for about 5 days before total RNAs were harvested for microarray analysis. N-Ras was silenced by shRNA or oncogenic N-Ras (G12D) was overexpressed in basal-like SUM102PT, SUM149PT and claudin-low SUM159PT cells.

2015-06-06 | E-GEOD-61768 | biostudies-arrayexpress

RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming through a paracrine process

Project description:The distinct frequency of activation of the RAS/MAPK signaling pathway in human cancers suggests a context-dependent cellular state of vulnerability to RAS transformation. While uncommon in breast cancers, oncogenic activation of this pathway is frequent in claudin-low (CL) tumors, a subtype of breast malignancies enriched in features of epithelial-mesenchymal transition (EMT), suggesting an interplay between RAS activation and EMT. Using inducible models of human mammary epithelial cells, we show that RAS-mediated transformation relies upon cellular reprogramming governed by the EMT-inducing transcription factor ZEB1. The path to ZEB1 induction involves a paracrine process: cells entering a senescent state following RAS induction release proinflammatory cytokines, notably IL-6 and IL1 which promote ZEB1 expression and activity in neighboring cells, thereby fostering their malignant transformation. Collectively, our findings unveil a previously unprecedented role for senescence in bridging RAS activation and EMT over the course of malignant transformation of human mammary epithelial cells.

2024-02-16 | GSE201536 | GEO

EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [mouse]

Project description:The newly identified claudin-low subtype of cancer is believed to represent the most primitive breast malignancies, having arisen from transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this hypothesis, we show both in vitro and in vivo that transcription factors inducing epithelial-mesenchymal transition can drive the development of claudin-low tumors from differentiated mammary epithelial cells, by playing a dual role in cell transformation and dedifferentiation. Gene expression profiles of three independent Twist1 + Ras- transgenic mouse-derived metaplastic breast tumors (Breast Tumor A, B and C) and of two luminal MMTV-ERBB2/Neu-breast tumor-derived cell lines (1 and 2) were determined.

2012-07-23 | E-GEOD-32904 | biostudies-arrayexpress

Characterization of Cell Lines Derived from Breast Cancers and Normal Mammary Tissues for the Study of the Intrinsic Molecular Subtypes

Project description:Five molecular subtypes (Luminal A/B, HER2-enriched, Basal-like, and Claudin-low) with clinical implications have been identified. In this report, we evaluated molecular and phenotypic relationships of a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs) and human mammary epithelial cells (HMECs) with (1) breast tumors, (2) normal breast cell-enriched subpopulations and (3) human embryonic stem cells (hESCs) and bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in vitro, except for the Luminal A. Secondly, we observed that cell lines recapitulate the differentiation hierarchy observed in the mammary gland, with Claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, Basal-like cells showing a luminal progenitor phenotype, and Luminal B cells showing a luminal phenotype. Thirdly, we identified Basal-like and highly migratory Claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143 and HCC38). Interestingly, both subpopulations within SUM149PT where found to have Tumor Initiating Cell (TIC) features, but the Basal-like subpopulation grew faster than the Claudin-low subpopulation. Finally, Claudin-low BCCLs were found to resemble the phenotype of hMSCs, whereas hESCs cells were found to have an epithelial phenotype without basal and luminal differentiation. The results presented here should help improve our understanding of the cell line model system through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts. reference x sample

2013-10-29 | E-GEOD-50470 | biostudies-arrayexpress

Isolation of subtype-specific N-Ras responsive genes in basal-like breast cancer cells

2015-06-06 | GSE61768 | GEO

KRAS and YAP1 converge to regulate EMT and tumor survival

Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.

2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress

Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer

Project description:In breast cancer, gene expression analyses have defined five tumor subtypes, each of which has unique biologic and prognostic features. Here, we characterize the recently identified claudin-low tumor subtype as showing low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes, and cancer stem cell–like features. Clinically, most claudin-low tumors are poorprognosis estrogen receptor–negative, progesterone receptor–negative, and human epidermal growth factor receptor 2–negative (triple-negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Moreover, we show that a group of highly used breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell. These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines.

2010-06-15 | GSE18229 | GEO

KRAS and YAP1 converge to regulate EMT and tumor survival

2014-07-27 | GSE56175 | GEO

Characterization of Cell Lines Derived from Breast Cancers and Normal Mammary Tissues for the Study of the Intrinsic Molecular Subtypes

2013-10-29 | GSE50470 | GEO