Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA316483 | ENA |
REPOSITORIES: ENA
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Project description:Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development. AKPK1 and ERN1 gene expression was knocked down in the MDA-MB-468 breast cancer cell line in duplicate by either siRNA or shRNA and tested in vitro for proliferation and differentiation.
2016-10-27 | E-GEOD-79630 | biostudies-arrayexpress
Project description:Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.
2016-10-27 | GSE79630 | GEO
Project description:The differentiation of stem-like cells of tumors may contribute to the cellular heterogeneity of breast cancers. We report the propagation of highly enriched mouse mammary cancer stem cells that retain the potential to differentiate both in vivo and in culture and their use to identify chemical compounds that influence both self-renewal and differentiation. We identify epithelial tumor initiating cells (ETIC) that expresses lineage markers of both basal and luminal mammary cell lineages and retains the potential to generate heterogeneous tumors similar to the tumor of origin from even single cells. ETIC can progress through a Rho associated coil-coil protein kinase 1 (ROCK1) dependent, epithelial to mesenchymal transition to generate a second cell type capable of initiating tumors of limited heterogeneity. The propagation of ETIC will increase the opportunities for identifying new therapeutic compounds that may inhibit or prevent progression of some types of breast cancer. These data compare the gene expression pattern of ETIC and MTIC. Total RNA obtained from ETIC and MTIC cells, allowing the comparison of gene expression patterns and the selection of potential targets.
2012-09-01 | E-GEOD-33433 | biostudies-arrayexpress
Project description:The differentiation of stem-like cells of tumors may contribute to the cellular heterogeneity of breast cancers. We report the propagation of highly enriched mouse mammary cancer stem cells that retain the potential to differentiate both in vivo and in culture and their use to identify chemical compounds that influence both self-renewal and differentiation. We identify epithelial tumor initiating cells (ETIC) that expresses lineage markers of both basal and luminal mammary cell lineages and retains the potential to generate heterogeneous tumors similar to the tumor of origin from even single cells. ETIC can progress through a Rho associated coil-coil protein kinase 1 (ROCK1) dependent, epithelial to mesenchymal transition to generate a second cell type capable of initiating tumors of limited heterogeneity. The propagation of ETIC will increase the opportunities for identifying new therapeutic compounds that may inhibit or prevent progression of some types of breast cancer. These data compare the gene expression pattern of ETIC and MTIC.
2012-09-01 | GSE33433 | GEO
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned two CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively. Rather than CD44+/CD24-,Basal B (G4) cells, only CD44hi/CD24lo, epithelioid Basal A (A4) cells retained a tumor-initiating capacity in NOG mice, form mammospheres and exhibit resistance to standard chemotherapy. Microarray data obtained from Affymetrix Human Gene 1.0 ST Array Five replicates of A4 and 5 replicates of G4
2012-06-11 | E-GEOD-32455 | biostudies-arrayexpress
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned two CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively. Rather than CD44+/CD24-,Basal B (G4) cells, only CD44hi/CD24lo, epithelioid Basal A (A4) cells retained a tumor-initiating capacity in NOG mice, form mammospheres and exhibit resistance to standard chemotherapy. Microarray data obtained from Affymetrix Human Gene 1.0 ST Array
2012-06-12 | GSE32455 | GEO
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively:CD44+/CD24-,Basal B (G4, H6) cells and CD44hi/CD24lo epithelioid Basal A (A4, AB) cells. Seven replicates of A4, seven replicates of G4, three replicates of AB, three replicates of H6
2015-04-30 | E-GEOD-59281 | biostudies-arrayexpress
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively:CD44+/CD24-,Basal B (G4, H6) cells and CD44hi/CD24lo epithelioid Basal A (A4, AB) cells.
2015-04-30 | GSE59281 | GEO
Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a M-bM-^@M-^\bi-lineageM-bM-^@M-^] differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition. Total of four treatments (HCC70 cells stably expressing shEZH2, shEED, or EZH2 cDNA, and MDA-MB-468 cells stably expressing shEZH2) were done in duplicates, each with its own control.
2012-09-21 | E-GEOD-36939 | biostudies-arrayexpress
Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a “bi-lineage” differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.
2012-09-21 | GSE36939 | GEO