Expression data from premalignant breast cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE7377 | GEO | 2007/03/28
SECONDARY ACCESSION(S): PRJNA100411
REPOSITORIES: GEO
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Project description:Enlargement of normal terminal duct lobular units (TDLUs) by hyperplastic columnar epithelial cells is one of the most common abnormalities of growth in the adult female human breast. These hyperplastic enlarged lobular units (HELUs) are important clinically as the earliest histologically identifiable potential precursor of breast cancer. The causes of the hyperplasia are unknown but may include estrogen-simulated growth mediated by estrogen receptor alpha, which is highly elevated in HELUs and may be fundamental to their development. This study used DNA microarray technology and RNA from microdissected pure epithelial cells to learn more about changes in gene expression and molecular pathways associated with the development of HELUs from TDLUs Experiment Overall Design: Samples for the microarray studies were derived from 8 formalin-fixed paraffin-embedded tissue (FFPET) biopsies containing paired normal TDLUs and well-developed HELUs from non-cancerous adult female human breasts obtained within the past 3 years. Populations of nearly pure (>95%) epithelial cells were isolated from the TDLUs and HELUs in each biopsy (approximately 25,000 cells/sample) by laser capture microdissection (LCM)
2009-04-23 | E-GEOD-7377 | biostudies-arrayexpress
Project description:Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor a expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the posttranscriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. MiR-27a, miR-92a and let-7c were among the identified downregulated epithelial miRNAs and their functions were delineated in unique CCH derived cells suggesting pro-apoptotic and anti-proliferative properties for the selected miRNAs and that downregulation of let-7c in CCH cells potentially increased proliferation via Myb. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding TDLUs, and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes. Global miRNA expression was also examined both epithelial and stroma of one patient displaying TDLU, CCH and additional invasive breast cancer. The miRNA signatures identified in CCH indicate concordant early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.
2014-07-15 | GSE46198 | GEO
Project description:• Atypical hyperplasias (AH) provide insights into early changes that may predispose breast epithelial cells to oncogenic transformation. • Of genes associated with premalignancy in prior studies, only mRNA levels of ESR1 and SFRP1 were detected in the present study. • Transcriptional profiling defined signatures distinguishing atypical hyperplasias. The patterns of expression were similar among hyperplastic lesions of lobular and ductal phenotype suggesting a common set of alterations underlying both lesions. Pathway analyses identified elevated expression of estrogen receptor alpha, androgen receptor and EGFR receptors and Rho signaling as central events nodes in the pathways altered in AH. • A set of 43 genes were identified as common targets using 2 different algorithms to detect signatures associated with AH. Knockdown of SFRP1 in a TERT immortalized breast epithelial cell line resulted in 14 genes from this signature being either up-regulated or down-regulated as observed in the expression profiles from AH. • The results demonstrate a signature of genes representing alterations that are common to the development of hyperplasias in both ductal and lobular epithelium. Loss of SFRP1 expression is a key player underlying the transcriptional changes in AH that directs a module of genes that can be used to improve reproducibility of diagnosis of AH.
2020-04-10 | GSE118432 | GEO
Project description:Background: Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics. Methods: Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells’ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells. Results: hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling. Conclusions: The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.
2020-09-30 | GSE153646 | GEO
Project description:We present an organoid regeneration assay in which freshly dissociated human mammary epithelial cells from healthy donors are grown in adherent/rigid or floating/compliant collagen I gels. In both conditions, luminal progenitors (CD49f+EpCAM+) form spheres, whereas basal cells (CD49fhiEpCAM-) generate branched ductal structures. However, in compliant but not rigid collagen gels, branching ducts form alveoli at their tips, express basal and luminal markers at correct positions and display contractility, which is required for alveologenesis. Thereby, branched structures generated in compliant collagen gels resemble terminal ductal-lobular units (TDLUs), the functional units of the mammary gland. Moreover, the membrane metallo-endopeptidase CD10 as an additional surface marker enriches for TDLU-formation and reveals the presence of stromal cells within the CD49fhiEpCAM- population. In summary, we describe a defined in vitro assay system to quantify cells with regenerative potential and systematically investigate their interaction with the physical environment at distinct steps of morphogenesis. Comparison of three cell populations derived from FACS-sorted primary human mammary epithelial cells: luminal progenitors, CD10+ basal cells and CD10- basal cells.
2015-07-02 | E-GEOD-64248 | biostudies-arrayexpress
Project description:Normal-appearing epithelium of cancer patients can harbor occult genetic abnormalities. Data comprehensively comparing gene expression between histologically normal breast epithelium of breast cancer patients and cancer-free controls are limited. The present study compares global gene expression between these groups. We performed microarrays using RNA from microdissected histologically normal terminal ductal-lobular units (TDLU) from 2 groups: (i) cancer normal (CN) (TDLUs adjacent to untreated ER1 breast cancers (n = 14)) and (ii) reduction mammoplasty (RM) (TDLUs of age-matched women without breast disease (n = 15)). Cyber-T identi?ed differentially expressed genes. Quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC), and comparison to independent microarray data including 6 carcinomas in situ (CIS), validated the results. Gene ontology (GO), UniProt and published literature evaluated gene function. About 127 probesets, corresponding to 105 genes, were differentially expressed between CN and RM (p < 0.0009, corresponding to FDR <0.10). 104/127 (82%) probesets were also differentially expressed between CIS and RM, nearly always (102/104 (98%)) in the same direction as in CN vs. RM. Two-thirds of the 105 genes were implicated previously in carcinogenesis. Overrepresented functional groups included transcription, G-protein coupled and chemokine receptor activity, the MAPK cascade and immediate early genes. Most genes in these categories were under-expressed in CN vs. RM. We conclude that global gene expression abnormalities exist in normal epithelium of breast cancer patients and are also present in early cancers. Thus, cancer-related pathways may be perturbed in normal epithelium. These abnormalities could be markers of disease risk, occult disease, or the tissueâs response to an existing tumor. Experiment Overall Design: 29 samples from histologically normal microdissected breast epithelium are included in this series. 14 samples are from epithelium adjacent to a breast tumor, 15 samples were obtained from patients undergoing reduction mammoplasty without apparent breast cancer
2008-06-16 | E-GEOD-9574 | biostudies-arrayexpress
Project description:We present an organoid regeneration assay in which freshly dissociated human mammary epithelial cells from healthy donors are grown in adherent/rigid or floating/compliant collagen I gels. In both conditions, luminal progenitors (CD49f+EpCAM+) form spheres, whereas basal cells (CD49fhiEpCAM-) generate branched ductal structures. However, in compliant but not rigid collagen gels, branching ducts form alveoli at their tips, express basal and luminal markers at correct positions and display contractility, which is required for alveologenesis. Thereby, branched structures generated in compliant collagen gels resemble terminal ductal-lobular units (TDLUs), the functional units of the mammary gland. Moreover, the membrane metallo-endopeptidase CD10 as an additional surface marker enriches for TDLU-formation and reveals the presence of stromal cells within the CD49fhiEpCAM- population. In summary, we describe a defined in vitro assay system to quantify cells with regenerative potential and systematically investigate their interaction with the physical environment at distinct steps of morphogenesis.
2015-07-02 | GSE64248 | GEO
Project description:Columnar cell hyperplasia (CCH) is the first histologically identifiable lesion in the breast with premalignant potential. Altered miRNA expression in the stroma surrounding CCH compared to normal tissue was discovered. The effect of upregulation of one specific miRNA was investigated by gene expression array in human mammary fibroblasts as well as in epithelial CCH cells coculterd with miR-132 oversexpressing human mammary fibroblasts. We used microarrays to detail the effects of miR-132 in human mammary fibroblasts and identified multiple altered genes and gene pathways both in the fibroblasts and in cocultured human mammary epithelial CCH cells.
2014-07-15 | GSE46197 | GEO
Project description:Gene expression profiling of normal tissues after curative radiotherapy was carried out to investigate the pathogenesis of late radiation injury in humans. Irradiated and control normal breast tissue was collected from patients undergoing bilateral mastectomy for ipsilateral tumour relapse or prophylaxis following radiotherapy for breast cancer. Using P.A.L.M. laser capture microdissection (LCM) of frozen sections, breast tissue was separated into an epithelial compartment (terminal duct lobular units and ducts) and a stromal compartment (remaining tissue). RNA was extracted, amplified and hybridised to a 20k cDNA array against a breast tissue reference RNA. Expression profiles of irradiated vs control breast were compared for each tissue compartment
2008-08-12 | E-TABM-419 | biostudies-arrayexpress
Project description:Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine micro-collection of uncultured organoids and single cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal ductal lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes reveals a strong correlation between normal breast K15+ ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.
| EGAS00001005963 | EGA