Suppressed cytokine and chemokine transcriptional signatures in mammary stem/progenitor cells are associated with dietary protection against Wnt1-driven mammary tumorigenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE37849 | GEO | 2014/06/30
SECONDARY ACCESSION(S): PRJNA163887
REPOSITORIES: GEO
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Project description:Maintenance and propagation of breast cancer stem cells (BCSCs) is mediated via cytokine and growth factor networks. Direct in vivo linkage between dietary regulation of mammary stem (MaSC)/progenitor cell numbers and protection from breast cancer has not been reported. Here, we investigated the effect of post-weaning intake of soy protein isolate (SPI) relative to the control casein (CAS) diet on the stem/progenitor population and tumor formation in MMTV-Wnt1-Transgenic (Wnt1-Tg) female mice. Gene expression profile of the basal (MaSC-enriched) sub-population in preneoplastic Wnt1-Tg mice demonstrated a stem cell-like expression pattern and markedly suppressed expression of inflammatory cytokines, C-X-C family chemokines, and metastasis-associated genes with dietary SPI exposure. four Samples: two CAS diet, two SPI diet
2014-06-30 | E-GEOD-37849 | biostudies-arrayexpress
Project description:Identification and transcriptome analysis of mammary stem cells (MaSC) are important steps toward understanding the molecular and cellular bases of mammary epithelial growth, homeostasis and tissue repair. We identified MaSC based upon their ability to retain bromodeoxyuridine (BrdU) for an extended period. Using laser microdissection, we isolated four categories of cells from the mammary epithelium of female bovine calves. These categories included label retaining epithelial cells (LREC) from the basal layer (LRECb), basal control cells (ECb), LREC from embedded layers (LRECe) and embedded control cells (ECe). Microarray analysis revealed 592 genes that were differentially expressed between LRECb and ECb, and 110 genes between LRECe and ECe. Our analysis supported classification of LRECb as MaSC and LRECe as progenitor cells. Enriched expression of genes in LRECb were associated with stem cell attributes and identified enrichment of Wnt, Notch and MAPK pathways of self renewal and proliferation. Genes expressed in LRECe revealed retention of some stem-like properties along with up-regulation of differentiation factors and the Notch pathway involved in lineage commitment. The basal epithelium provided for the stem cell niche, characterized as a microenvironment containing numerous survival and proliferation factors, growth suppressors and chromatin modifiers in balance state. We conclude that BrdU label retention identifies stem and progenitor cells, wherein MaSC are located in the basal epithelial layer and committed progenitor cells are localized in more apical layers. Results provide novel candidate markers for bovine MaSC with potential applicability to the study of MaSC in other species.
2012-06-03 | GSE31541 | GEO
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
Project description:Bovine mammary stem cells (MaSC) are a source of ductal and lobulo-alveolar tissue during development of mammary gland and its remodeling in repeating lactation cycles. We hypothesize that the number of MaSC, their molecular properties and interactions with their niche may be essential to determine the mammogenic potential in heifers. To verify this hypothesis we compared the number of MaSC and transcriptomic profile in mammary tissue of 2-year-old, non-pregnant dairy (Holstein-Friesian) and beef (Limousin) heifers. For identification and quantification of putative stem/progenitor cells in mammary tissue sections scanning cytometry was used with a new combination of MaSC molecular markers: stem cell antigen-1 (Sca-1) and fibronectin type III domain containing 3B (FNDC3B) protein. Double labeled cells were located mainly in the basal layers of mammary epithelium. Cytometric analysis of Sca-1pos FNDC3Bpos cells revealed significantly higher number in HF (2.94M-BM-10.35%) than in LM (1.72M-BM-10.20%) heifers. More advanced development of mammary tissue in HF heifers was accompanied by higher expression of intramammary hormones, growth factors, cytokines, chemokines and transcription regulators. The model of transcriptomic niche favorable for MaSC was associated with regulation of genes involved in MaSC maintanence, self renewal, proliferation, migration, differentiation, mammary tissue remodeling, angiogenesis, regulation of adipocyte differentiation, lipid metabolism and steroid and insulin signaling. In conclusion the high mammogenic potential in postpubertal dairy heifers is facilitated by a higher number of MaSC and up-regulation of mammary auto-, paracrine factors representing MaSC niche. Keywords: stem/progenitor cells, transcriptomics, mammary gland, dairy and beef heifers Two-condition experiment, LIM vs. HF. Pulled quarters of mammary glands form 10 LIM heifers (test) and 10 HF heifers (reference). Sample 3 and 4 are dye swaps.
2013-06-16 | E-GEOD-47816 | biostudies-arrayexpress
Project description:Bovine mammary stem cells (MaSC) are a source of ductal and lobulo-alveolar tissue during development of mammary gland and its remodeling in repeating lactation cycles. We hypothesize that the number of MaSC, their molecular properties and interactions with their niche may be essential to determine the mammogenic potential in heifers. To verify this hypothesis we compared the number of MaSC and transcriptomic profile in mammary tissue of 2-year-old, non-pregnant dairy (Holstein-Friesian) and beef (Limousin) heifers. For identification and quantification of putative stem/progenitor cells in mammary tissue sections scanning cytometry was used with a new combination of MaSC molecular markers: stem cell antigen-1 (Sca-1) and fibronectin type III domain containing 3B (FNDC3B) protein. Double labeled cells were located mainly in the basal layers of mammary epithelium. Cytometric analysis of Sca-1pos FNDC3Bpos cells revealed significantly higher number in HF (2.94±0.35%) than in LM (1.72±0.20%) heifers. More advanced development of mammary tissue in HF heifers was accompanied by higher expression of intramammary hormones, growth factors, cytokines, chemokines and transcription regulators. The model of transcriptomic niche favorable for MaSC was associated with regulation of genes involved in MaSC maintanence, self renewal, proliferation, migration, differentiation, mammary tissue remodeling, angiogenesis, regulation of adipocyte differentiation, lipid metabolism and steroid and insulin signaling. In conclusion the high mammogenic potential in postpubertal dairy heifers is facilitated by a higher number of MaSC and up-regulation of mammary auto-, paracrine factors representing MaSC niche. Keywords: stem/progenitor cells, transcriptomics, mammary gland, dairy and beef heifers
2013-06-16 | GSE47816 | GEO
Project description:Identification and transcriptome analysis of mammary stem cells (MaSC) are important steps toward understanding the molecular and cellular bases of mammary epithelial growth, homeostasis and tissue repair. We identified MaSC based upon their ability to retain bromodeoxyuridine (BrdU) for an extended period. Using laser microdissection, we isolated four categories of cells from the mammary epithelium of female bovine calves. These categories included label retaining epithelial cells (LREC) from the basal layer (LRECb), basal control cells (ECb), LREC from embedded layers (LRECe) and embedded control cells (ECe). Microarray analysis revealed 592 genes that were differentially expressed between LRECb and ECb, and 110 genes between LRECe and ECe. Our analysis supported classification of LRECb as MaSC and LRECe as progenitor cells. Enriched expression of genes in LRECb were associated with stem cell attributes and identified enrichment of Wnt, Notch and MAPK pathways of self renewal and proliferation. Genes expressed in LRECe revealed retention of some stem-like properties along with up-regulation of differentiation factors and the Notch pathway involved in lineage commitment. The basal epithelium provided for the stem cell niche, characterized as a microenvironment containing numerous survival and proliferation factors, growth suppressors and chromatin modifiers in balance state. We conclude that BrdU label retention identifies stem and progenitor cells, wherein MaSC are located in the basal epithelial layer and committed progenitor cells are localized in more apical layers. Results provide novel candidate markers for bovine MaSC with potential applicability to the study of MaSC in other species. Five Holstein heifers were injected with bromodeoxyuridine (BrdU) for five consecutive days and sacrificed 45 days later, at which time mammary samples were obtained and processed. Cryosections were prepared and immunostained to detect epithelial cells that retained BrdU label (LREC). Four classes of cells were excised by laser microdissection, which included LREC and control cells in the basal and in the suprabasal layers of the mammary epithelium. For each cell type, cells were lysed, RNA was reverse transcribed and cDNA amplified for microarray analysis. Twenty microarrays were utilized for sample hybridization and another array for hybridization of amplified cDNA from a water blank.
2012-06-02 | E-GEOD-31541 | biostudies-arrayexpress
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.
2014-10-23 | GSE56391 | GEO
Project description:The Wnt gene family is an evolutionarily conserved group of proteins that regulate cell growth, differentiation, and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed to be an attractive drug target, especially in the basal-like subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt based therapeutics, however, has been slowed in part by a limited understanding of the context dependent nature with which these aberrations influence breast tumorigenesis. We recently reported that MMTV-Wnt1 mice, which are an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx. Here, we extend this initial observation and show that Wnt1-EarlyEx tumors had high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors had a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors also had primarily Cd49fpos/Epcamneg FACS profiles, but were unable to be serially transplanted into wild-type FVB female mice. Wnt1-LateEx tumors, conversely, had a bloody gross pathology, which was highlighted by the presence of ‘blood lakes’ by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitely shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors. Importantly, these subtypes differ in their therapeutic response to an EGFR inhibitor, suggesting that a subset of human tumors with aberrant Wnt signaling may also respond to erlotinib.
2019-06-26 | GSE118163 | GEO
Project description:The Wnt gene family is an evolutionarily conserved group of proteins that regulate cell growth, differentiation, and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed to be an attractive drug target, especially in the basal-like subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt based therapeutics, however, has been slowed in part by a limited understanding of the context dependent nature with which these aberrations influence breast tumorigenesis. We recently reported that MMTV-Wnt1 mice, which are an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx. Here, we extend this initial observation and show that Wnt1-EarlyEx tumors had high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors had a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors also had primarily Cd49fpos/Epcamneg FACS profiles, but were unable to be serially transplanted into wild-type FVB female mice. Wnt1-LateEx tumors, conversely, had a bloody gross pathology, which was highlighted by the presence of ‘blood lakes’ by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitely shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors. Importantly, these subtypes differ in their therapeutic response to an EGFR inhibitor, suggesting that a subset of human tumors with aberrant Wnt signaling may also respond to erlotinib.
2019-06-26 | GSE118161 | GEO
Project description:The Wnt gene family is an evolutionarily conserved group of proteins that regulate cell growth, differentiation, and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed to be an attractive drug target, especially in the basal-like subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt based therapeutics, however, has been slowed in part by a limited understanding of the context dependent nature with which these aberrations influence breast tumorigenesis. We recently reported that MMTV-Wnt1 mice, which are an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx. Here, we extend this initial observation and show that Wnt1-EarlyEx tumors had high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors had a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors also had primarily Cd49fpos/Epcamneg FACS profiles, but were unable to be serially transplanted into wild-type FVB female mice. Wnt1-LateEx tumors, conversely, had a bloody gross pathology, which was highlighted by the presence of ‘blood lakes’ by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitely shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors. Importantly, these subtypes differ in their therapeutic response to an EGFR inhibitor, suggesting that a subset of human tumors with aberrant Wnt signaling may also respond to erlotinib.
2019-06-26 | GSE118162 | GEO