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Tumor Suppressor Role for the c-Myb Oncogene in Luminal Breast Cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21371 | GEO | 2010/10/15

SECONDARY ACCESSION(S): PRJNA126079

REPOSITORIES: GEO

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Tumor Suppressor Role for the c-Myb Oncogene in Luminal Breast Cancer

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

Homo sapiens

Project description:Tumor Suppressor Role for the c-Myb Oncogene in Luminal Breast Cancer

| PRJNA126079 | ENA

Transcription profiling of PTEN-deficiency in luminal MMTV-ErbB-2 mouse model to investigate its effect on mammary tumorigenesis and metastasis

Project description:Overexpression and/or amplification of the ErbB-2 oncogene, as well as inactivation of the tumor suppressor PTEN, are two important genetic events in human breast carcinogenesis. To address the biological impact of conditional inactivation of PTEN on ErbB-2-induced mammary tumorigenesis, we generated a novel transgenic mouse model that utilizes the MMTV promoter to directly couple expression of activated ErbB-2 and Cre recombinase to the same mammary epithelial cell (MMTV-NIC). Disruption of PTEN in the mammary epithelium of the MMTV-NIC model system dramatically accelerated the formation of multifocal and highly metastatic mammary tumors, which exhibit homogenous pathology. PTEN-deficient/NIC tumorigenesis was associated with an increase in angiogenesis. Moreover, inactivation of PTEN in the MMTV-NIC mouse model resulted in hyperactivation of the PI3K/Akt signalling pathway. However, like the parental strain, tumors obtained from PTEN-deficient/NIC mice displayed histopathological and molecular features of the luminal-like subtype of breast cancer. Taken together, our findings provide important implications in understanding the molecular determinants of mammary tumorigenesis driven by PTEN deficiency and ErbB-2 activation, and could provide a valuable tool for testing the efficacy of therapeutic strategies that target these critical signalling pathways. Experiment Overall Design: Common reference design. 9 samples (including 2 normal tissue and 7 tumor tissue samples) replicated twice as dye swaps, generating a total of 18 arrays.

2009-07-03 | E-GEOD-13916 | biostudies-arrayexpress

wnt1-induced mammary tumor from Rarb KO mice vs. those from Rarb wt (control)

Project description:Previously we have demonstrated that inactivation of retinoic acid receptor beta (Rarb) in the mouse results in a protective effect against ErbB2-induced mammary gland tumorigenesis although Rarb has been reported as a tumor suppressor before. In the current study, we further confirmed that ablation of Rarb has a very similar impact on Wnt1-induced mammary gland tumorigenesis as those on ErbB2-induced mammary gland tumorigenesis. Nevertheless, the mechanisms by which Rarb confers its effects on tumor progression is quite different although both involving in tumor microenvironment (TME) remodeling. In the Wnt1 tumors, ectopic wnt1 produced by malignant luminal cells activates nearby stromal cells by a paracrine manner. In return, the stromal cells secreted IGF1 to regulate the growth of tumor cells. There is a need of Rarb expression in this interaction. Deletion of Rarb inhibits both wnt1/β-catenin signaling and IGF1/Akt axis in the myoepithelial tumor cells which results in the suppression of epithelial-mesenchymal transition (EMT) in these tumors. Since wnt1 tumors resemble basal-like breast cancer with a poor clinical prognosis in which EMT is one of the most important way for tumor cells to survive against standard treatment and to go to metastasis, we propose that (1) the stromal gene expression signature of Rarb ablation in wnt1 tumors could have some clinical value in predicting the breast cancer outcome; and (2) Rarb antagonist might be a potential therapeutic strategy in EMT-driven aggressive cancers such as basal-like breast cancer. Laser capture microdissection (LCM) was performed to separate the mammary tumor samples into epithelial cell compartment and stromal cell compartment. Transcriptional profiling of the two compartments were investigated by microarray analysis.

2014-10-23 | E-GEOD-56391 | biostudies-arrayexpress

PTEN-deficiency in luminal MMTV-ErbB-2 mouse model results in dramatic acceleration in mammary tumorigenesis/metastasis

2009-06-29 | GSE13916 | GEO

Ezh2 promotes mammary tumor initiation through epigenetic regulation of the Wnt and mTORC1 signaling pathways (ChIP-Seq)

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

Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways (RNA-Seq)

2023-07-15 | GSE235145 | GEO

Rb deletion in mammary stem/progenitor epithelium induces tumors with features of luminal-B or basal-like breast cancer

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

Regulation of mammary luminal cell differentiation and tumorigenesis by p38α

Project description:Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we provide evidence that the protein kinase p38a is required for the differentiation of luminal progenitor cells through modulation of the transcription factors Runx1 and Foxa1. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38a downregulation in mammary epithelial cells reduces tumorigenesis, which correlates with reduced numbers of tumor-initiating cells. Our results identify p38a as a key regulator of luminal progenitor cell fate that facilitates mammary tumor formation.

2017-12-28 | GSE92877 | GEO

wnt1-induced mammary tumor from Rarb KO mice vs. those from Rarb wt (control)

2014-10-23 | GSE56391 | GEO

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