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Elucidating the gene expression profiles of human mammary subpopulations

ABSTRACT: The organisation of the mammary epithelial cell hierarchy and how these cells relate to the presentation of human breast tumours is poorly understood. Our results demonstrate that the luminal cell compartment of the mouse mammary gland can be resolved into terminally differentiated oestrogen receptor (ER)+ luminal cells, ER+ luminal progenitors and ER- luminal progenitors. The ER+ luminal progenitors are unique in regards to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared to the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation that is composed of terminally differentiated luminal cells and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one third of human breast samples examined contained an additional population that had a luminal progenitor phenotype, but is characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. Gene expression profiling demonstrates that the ER- luminal progenitors in the mouse and the undifferentiated ALDH+ luminal progenitors in the human have gene signatures that resemble those obtained from basal-like breast tumours. Overall, our work reveals a more defined mammary cell hierarchy, which may in turn provide greater insight into the aetiology of breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35399 | GEO | 2012/10/11

SECONDARY ACCESSION(S): PRJNA152785

REPOSITORIES: GEO

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Elucidating the gene expression profiles of human mammary subpopulations

Project description:The organisation of the mammary epithelial cell hierarchy and how these cells relate to the presentation of human breast tumours is poorly understood. Our results demonstrate that the luminal cell compartment of the mouse mammary gland can be resolved into terminally differentiated oestrogen receptor (ER)+ luminal cells, ER+ luminal progenitors and ER- luminal progenitors. The ER+ luminal progenitors are unique in regards to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared to the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation that is composed of terminally differentiated luminal cells and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one third of human breast samples examined contained an additional population that had a luminal progenitor phenotype, but is characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. Gene expression profiling demonstrates that the ER- luminal progenitors in the mouse and the undifferentiated ALDH+ luminal progenitors in the human have gene signatures that resemble those obtained from basal-like breast tumours. Overall, our work reveals a more defined mammary cell hierarchy, which may in turn provide greater insight into the aetiology of breast cancer. Normal human breast tissues from reduction mammoplasties were dissociated into single cells and the epithelial cell populations were flow sorted. Total RNA was extracted for each group in 11 independent patient samples.

2012-10-11 | E-GEOD-35399 | biostudies-arrayexpress

Gene expression profiles of normal human mammary cell subpopulations FACS sorted based on expression of CD49f and EpCAM

Project description:To delineate epithelial subpopulations in human mammary tissue, hematopoietic and endothelial cells were depleted from freshly isolated cell suspensions derived from reduction mammoplasties by fluorescence-activated cell sorting. The resultant Lin- population was fractionated into four distinct subpopulations using CD49f (α6-integrin) and epithelial cell adhesion molecule (EpCAM; also referred to as CD326 and ESA). Based on the immunohistochemical phenotype, and in vivo and in vitro functional assays, these subpopulations were identified as fibroblast-enriched stromal (CD49f -EpCAM-), mammary stem cell (MaSC)-enriched (CD49f hiEpCAM-), luminal progenitor (CD49f +EpCAM+), and mature luminal (CD49f –EpCAM+) cell subpopulations. Microarray profiling was used to derive gene expression signatures representative of these subpopulations using freshly sorted cells (>90% purity) from normal breast tissue. The four mammary cell subpopulations were found to have distinct gene expression profiles.

2009-07-09 | GSE16997 | GEO

Gene expression profiles of normal human mammary cell subpopulations FACS sorted based on expression of CD49f and EpCAM

Project description:To delineate epithelial subpopulations in human mammary tissue, hematopoietic and endothelial cells were depleted from freshly isolated cell suspensions derived from reduction mammoplasties by fluorescence-activated cell sorting. The resultant Lin- population was fractionated into four distinct subpopulations using CD49f (Î±6-integrin) and epithelial cell adhesion molecule (EpCAM; also referred to as CD326 and ESA). Based on the immunohistochemical phenotype, and in vivo and in vitro functional assays, these subpopulations were identified as fibroblast-enriched stromal (CD49f -EpCAM-), mammary stem cell (MaSC)-enriched (CD49f hiEpCAM-), luminal progenitor (CD49f +EpCAM+), and mature luminal (CD49f âEpCAM+) cell subpopulations. Microarray profiling was used to derive gene expression signatures representative of these subpopulations using freshly sorted cells (>90% purity) from normal breast tissue. The four mammary cell subpopulations were found to have distinct gene expression profiles. Four mammary cell subpopulations from three individual patient samples were analyzed.

2010-08-19 | E-GEOD-16997 | biostudies-arrayexpress

Project description:Genomic instability is a prominent driver of tumorigenesis. However, a significant fraction of human cancers display few genomic aberrations, suggesting alternative roads towards malignancy. Here, we show that the differentiation status of normal human mammary epithelial cells influences the early response to an oncogenic activation and determines the genetic routes towards tumorigenesis. Following an oncogenic insult, luminal progenitors and differentiated luminal cells undergo oxidative and DNA replication stress, initiating genomic instability. In contrast, mammary stem cells exhibit the innate capacity to withstand aberrant mitogenic activation, fostering malignant transformation. This property relies upon a pre-emptive program driven by the ZEB1 transcription factor and the methionine sulfoxide reductase MSRB3. The ZEB1-MSRB3 axis governs cellular pliancy and prevents the continuous formation of oncogene-induced DNA damage, leading to neoplasms with unique pathological features. These gene expression data correspond to the different subpopulations that compose the hierarchy of normal human mammary epithelial cells. These subpopulations were freshly isolated from mammary tissue, originating from reduction mammoplasties and flow sorted using four markers (EpCAM, CD10, CD49f, ALDH). Three subpopulations enriched in mammary stem cells (MaSCs) are designed as MaSC1, 2, 3; the luminal progenitor are designed as LP, and the mature luminal cells as mL1 and mL2.

2017-03-23 | E-MTAB-4145 | biostudies-arrayexpress

Genome Wide Expression of Mammary Epithelial Populations in Slug (SNAI2) WT vs Slug Null Mice

Project description:This experiment shows differential expression of genes in the luminal, basal and stromal subpopulations from SNAI2+/+ and SNAI2 LacZ/LacZ mammary epithelial cells. Luminal, basal and stromal populations were sorted from SNAI2+/+ and SNAI2 LacZ/LacZ mammary epithelial cells based on expression of CD49f and Epcam.

2014-03-08 | E-GEOD-55620 | biostudies-arrayexpress

Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast

Project description:Gene expression profiles of normal human mammary epithelial cell subsets enriched for luminal or myoepithelial characteristics on the basis of EpCAM and CD49f expression. Transcription profiles were compared between luminal- and myoepithelial-enriched human MEC subsets following 3D culture from 4 individuals. Gene expression profiles of normal human mammary epithelial cell subsets enriched for mature, luminal progenitor or bipotent progenitor-enriched characteristics on the bais of CD49f, MUC1, CD10, CD133 and Thy1 expression Transcription profiles were compared between unsorted, mature, luminal progenitor-enriched and bipotent progenitor-enriched human MEC subsets following 3D culture from 2 individuals.

2012-08-17 | GSE31429 | GEO

Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast

2012-08-17 | E-GEOD-31429 | biostudies-arrayexpress

Quantification of regenerative potential in primary human mammary epithelial cells

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

Gene expression profiles of epithelial and mesenchymal cell populations extracted from normal human breast tissue

Project description:Stromal-epithelial interactions play a fundamental role in tissue homeostasis, controlling cell proliferation and differentiation. The goals and objectives of this study were 1.) To generate gene expression profiles and identify signatures of freshly isolated, non-cultured, luminal epithelial or basal epithelial and CD10 positive or negative stromal cell populations from the human breast. 2.) Use the generated signatures to characterize and validate the molecular identity of human primary epithelial and stromal/mesenchymal breast cells maintained long-term in novel ex vivo culture conditions in serum free medium (previous study in our lab) Breast tissue from three different reduction mammoplasties was dissociated and single cells were labeled with antibodies against lineage markers (CD31, CD45 CD235ab), CD10, EpCAM, CD49f and DAPI. Different cell populations were identified, separated and sorted with a fluorescence activated cell sorter. Gene expression profiling of luminal epithelial (EpCAM+, CD49f+/-), basal epithelial (EPCAM-, CD49f+), CD10 negative and CD10 positive stromal cells was performed and distinct gene expression signatures for the four cell populations were identified.

2015-09-26 | GSE51200 | GEO

Functional and phenotypic characterizations of common syngeneic tumor cell lines as estrogen receptor positive breast cancer models

Project description:Estrogen receptor positive breast cancers (ER+ BCas) are the most common form of BCa and is increasing in incidence largely due to changes in reproductive practices in recent decades. Tamoxifen is prescribed as a component of standard of care endocrine therapy for treatment and prevention of ER+ BCa. However, it is poorly tolerated leading to low uptake of the drug in the preventative setting. Alternative therapies and preventatives for ER+ BCa are needed but development is hampered due to a paucity of syngeneic ER+ preclinical mouse models that allow pre-clinical experimentation in immunocompetent mice. Two ER positive models, J110 and SSM3, have been reported in addition to other tumor models occasionally shown to express ER (for example 4T1.2, 67NR, EO771, D2.0R and D2A1). Here we have assessed ER expression and protein levels in seven mouse mammary tumor cell lines and their corresponding tumors in addition to their cellular composition, tamoxifen sensitivity and molecular phenotype. By immunohistochemical assessment, SSM3 and to a lesser extent 67NR cells are ER+. Using flow cytometry and transcript expression we show that SSM3 cells are luminal in nature whilst D2.0R and J110 cells are stromal/basal. The remainder are also stromal/basal in nature; displaying a stromal or basal Epcam/CD49f FACS phenotype and stromal and basal gene expression signatures are overrepresented in their transcript profile. Consistent with a luminal identity for SSM3 cells, they also show sensitivity to tamoxifen in vitro and in vivo. In conclusion, the data indicates that the SSM3 syngeneic cell line is the only definitively ER+ mouse mammary tumor cell line widely available for pre-clinical research.

2023-03-16 | GSE226910 | GEO

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