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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

SUBMITTER: Morel AP

PROVIDER: S-ECPF-GEOD-32905 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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

Project description:The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT-inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell-like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation.

| S-EPMC3359981 | biostudies-literature

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

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 [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

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

2012-07-24 | GSE32905 | GEO

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

2012-07-24 | GSE32904 | GEO

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

2012-07-24 | GSE32727 | GEO

EMT tumorigenesis in the mouse mammary gland.

Project description:The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. In mice, most 'EMT' tumors have a spindle cell phenotype. The definition of EMT is controversial because spindle cell tumors are not common in humans, especially in human breast cancers. Spindle cell tumors of the mouse mammary gland have been observed for many years where they are usually classified as sarcomas or carcinosarcomas. Genetically engineered mice develop mammary spindle cell tumors that appear to arise in the epithelium and undergo EMT. To better understand the origin and evolution of these spindle cell tumors in progression and metastases, seven cohorts of spindle cell tumors from the archives of the University of California, Davis Mutant Mouse Pathology Laboratory were studied. This study provides experimental and immunohistochemical evidence of EMT showing that dual epithelial and mesenchymal staining of tumor spindle cells identifies some, but not all, EMT-type tumors in the mouse. This suggests that potential EMT tumors are best designated EMT-phenotype tumors.

| S-EPMC2754828 | biostudies-literature

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 entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. 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 stemness, mammary gland development, and claudin-low breast cancer formation.

| S-EPMC8550236 | biostudies-literature

Physical confinement induces malignant transformation in mammary epithelial cells.

Project description:The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics.

| S-EPMC7336132 | biostudies-literature

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