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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE32904 | GEO | 2012/07/24

SECONDARY ACCESSION(S): PRJNA154399

REPOSITORIES: GEO

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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

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

2012-07-24 | GSE32727 | GEO

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

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

Project description:This SuperSeries is composed of the following subset Series: GSE32727: EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [human] GSE32904: EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [mouse] Refer to individual Series

2012-07-23 | E-GEOD-32905 | 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

Defining the cellular precursors to human breast cancer

Project description:Human breast cancers are broadly classified based on their gene expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast, luminal (EpCAM+) and basal/myoepithelial (ME, CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer including ER+ and ER- tumors with luminal and basal-like characteristics, respectively, while transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is due in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues. 8 breast cell line samples

2011-09-21 | E-GEOD-30489 | biostudies-arrayexpress

An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Project description:The Epithelial–Mesenchymal Transition (EMT) and primary ciliogenesis induce stem cell properties in basal Mammary Stem Cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon intermediate EMT transition states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote BBS11-dependent ubiquitination and inactivation of a central signaling node, GLIS2. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the Mammary-Tumor-initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC biology, mammary gland development, and claudin-low breast cancer formation.

2021-10-05 | GSE173788 | GEO

Defining the cellular precursors to human breast cancer

2011-09-22 | GSE30489 | GEO

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

Project description: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.

2021-05-05 | GSE157333 | GEO

Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential

Project description:Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of the miR-200 family of microRNAs in regulating the epithelial state, stem-like properties, and therapeutic response in an in vivo primary, syngeneic p53null claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this claudin-low model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. MiR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion, and motility. Accordingly, induced miR200c expression also significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53null claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity, and metastatic potential in vivo. reference x sample

2015-06-22 | E-GEOD-62230 | biostudies-arrayexpress

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