Homo sapiens
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PROVIDER: PRJNA126079 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. RNAi knock-down of endogenous c-Myb levels in the MCF7 luminal breast tumor cell line increases tumorigenesis both in vitro and in vivo, suggesting a tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. These data describe, for the first time, a tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for understanding luminal tumorigenesis and for guiding treatment. refXsample
2010-10-15 | E-GEOD-21371 | biostudies-arrayexpress
Project description:BACKGROUND: The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). METHODOLOGY/PRINCIPAL FINDINGS: We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. Stable RNAi knock-down of endogenous c-Myb in the MCF7 luminal breast tumor cell line increased tumorigenesis both in vitro and in vivo, suggesting a possible tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature, comprised of both direct and indirect c-Myb target genes, and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. CONCLUSIONS/SIGNIFICANCE: These data describe, for the first time, a possible tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for the understanding of luminal tumorigenesis and for guiding treatment.
2010-10-15 | GSE21371 | GEO
Project description:LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite roles remain largely elusive. By characterizing its role in normal and cancerous luminal mammary epithelial cells (MECs), here we show that LSD1 is essential for maintaining differentiation and survival of luminal cells. LSD1-inhibition by both genetic and pharmacological approaches increases invasion of luminal breast cancer cells. Mechanistically, we find LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression and represses that of TRIM37, a histone H2A ubiquitin ligase and breast cancer oncoprotein. LSD1-loss leads to reduced expression of several cell junction genes (e.g., CDH1, VCL, CTNNA1), possibly via TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the increased MEC invasiveness associated with LSD1-inhibition can be blocked via TRIM37-inhibition.
2019-08-16 | GSE95165 | GEO
Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235145 | GEO
Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235144 | GEO
Project description:The retinoblastoma tumor suppressor, Rb, is implicated in luminal-B and basal-like breast carcinomas, yet its effect on mammary gland development and causal role in breast cancer subtypes remain undefined. Here we show that conditional deletion of Rb in mouse mammary epithelium led to expansion of the stem/progenitor cells and to focal acinar hyperplasia with squamous metaplasia. These uniform lesions progressed into histologically diverse, transplantable mammary adenocarcinomas and adenosquamous carcinomas with features of luminal-B or basal-like carcinomas. A subset of basal-like but none of the luminal-B tumors expressed mutant p53. These results demonstrate a causative role for Rb in the etiology of breast cancer subtypes and implicate p53 status as a determinant of tumor phenotype after Rb loss. Keywords: reference x sample Will be updated soon
2010-07-06 | E-GEOD-14457 | biostudies-arrayexpress
Project description:Glucocorticoid receptor (GR) is a ligand-inducible transcription factor with an intricate role in cancer biology. Using an in silico designed GR activity signature we show that GR is a tumor suppressor across diverse primary cancers. In breast cancer, GR activity status determines luminal identity, and importantly, relates to patients’ outcomes. We illustrate that GR suppresses tumor growth, mediated through its engagement with the estrogen receptor-α (ER). This steroid hormone receptor cross-talk leads to redistribution of ERα on chromatin, ultimately leading to expression of ZBTB16 gene. We define ZBTB16 as a transcriptional repressor and a tumor suppressor in ER-positive breast cancer. Importantly, highly aggressive ER-positive breast cancer cells displaying absence of GR activity can be eradicated if GR-induced gene repression is mimicked by inhibitors of the epigenetic pathway. In line with this, epigenetic regulators are highly expressed upon GR activity loss, leading to vulnerability of aggressive breast cancer cells to clinically available epigenetic inhibitors. Our findings indicate that GR functions as a tumor suppressor by repositioning ER to specific sites on chromatin, modulating targetable pathways, which has important implications for patients’ prognosis and therapeutic interventions.
2023-10-02 | PXD039209 | Pride
Project description:Frequent loss of heterozygosity (LOH) at 11q22-23 in breast cancer strongly suggests that this region contains a tumor suppressor gene, yet to be identified. We and others have shown Yes-associated protein (YAP), which is located at 11q22.2, transactivates the p53 family member p73 upon DNA damage, suggesting a tumor suppressive function for YAP. Our analysis of breast tumor tissues by immunohistochemistry (IHC) showed loss of YAP protein expression in great portion of breast cancers. We used microarray to look at the targte genes regulated by YAP in normal breast luminal cell and breast cancer cell lines. Experiment Overall Design: We generated stable cell lines by introducing control vector(pRS-IRES-GFP/pmig) or YAP shRNA(pRS-IRES-GFP-YAP/pmig-YAP) in a normal breast luminal cell line 1089 luminal and breast cancer cell lines MDA MB231. RAN was extracted and hybridized on Affymetrix microarrays.We looked for new target genes regulated by YAP in normal breast luminal cell and breast cancer cell lines.
2009-01-18 | E-GEOD-7700 | biostudies-arrayexpress
Project description:The retinoblastoma tumor suppressor, Rb, is implicated in luminal-B and basal-like breast carcinomas, yet its effect on mammary gland development and causal role in breast cancer subtypes remain undefined. Here we show that conditional deletion of Rb in mouse mammary epithelium led to expansion of the stem/progenitor cells and to focal acinar hyperplasia with squamous metaplasia. These uniform lesions progressed into histologically diverse, transplantable mammary adenocarcinomas and adenosquamous carcinomas with features of luminal-B or basal-like carcinomas. A subset of basal-like but none of the luminal-B tumors expressed mutant p53. These results demonstrate a causative role for Rb in the etiology of breast cancer subtypes and implicate p53 status as a determinant of tumor phenotype after Rb loss. Keywords: reference x sample
2010-07-07 | GSE14457 | GEO
Project description:Background: We have established a statistical approach on building a transcriptional regulatory network in silico at a global transcriptome scale. Here, we characterize clinical relevant gene activities regulated by a transcription factor-estrogen-related receptor gamma (ESRRG) via such approach. Methods: We measured gene expression relationship between ESRRG and its target gene via univariate coefficient of intrinsic dependence and Galton Pearson’s correlation coefficient. A few more bioinformatics tools were used for further investigation on ESRRG. Results: ESRRG is a negative determinant of lymphovascular invasion, lymph nodal category, stage, histological grade, nuclear pleomorphism and tubule formation in ER(+) infiltrating ductal carcinoma of breast. Interestingly, ESRRG was the only one in the final intersection of Venn Diagram analyses for determinants of those clinical indices. We established an ESRRG core network consisting of 118 probes. Both MYB and ARNT2 were up-regulated by ESRRG and in two ESRRG subnetworks (29 probes, 89 probes), respectively. We observed genes for tumor suppressive activities and responsiveness to anticancer treatments within ESRRG core network and a conserved protective role of ESRRG. Conclusions: ESRRG is a tumor suppressor typically for ER(+) breast cancer and up-regulates tumor suppressor genes mostly within ERα transcriptional regulatory network. An ESRRG core network reveals ESRRG to be a favorable marker and MYB to be the main partner for its cancer protective role during early tumor promotion. But, ARNT2 is an additional partner of ESRRG during early tumor progression. Impact: A core ESRRG transcriptional regulatory network indicates the major clinical impact of ESRRG. 181 surgical specimens of primary infiltrating ductal carcinoma (IDC) were obtained from patients who underwent surgery at National Taiwan University Hospital (NTUH) between 1998 and 2007. They include 90 ER(+) IDCs and 91 ER(-) IDCs. Tissue samples were excised, snap frozen in liquid nitrogen, and stored at -80℃. Breast cancer samples containing relatively pure cancer as defined by greater than 50% tumor cells per high-power field examined in an adjacent section of tumor sample were for this study (Lien HC, et al. Oncogene 2007; 26: 7859-71). Twenty five non-tumor samples were surgically taken from breast cancer patients in 181 IDC patients to generate 25 gene expression profiles as a control in this study. All patients had given informed consent according to the guidelines approved by the Institutional Review Board at NTUH. The matrix file linked to the bottom of this Series includes reanalyzed data from the 119 Samples of this Series and 87 Samples from Series GSE9309 and GSE17040.
2010-11-04 | E-GEOD-24124 | biostudies-arrayexpress