Mammary epithelial cells have lineage-rooted metabolic identities
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Dr. Thomas Kislinger Dr. Rama Khokha
PROVIDER: MSV000087042 | MassIVE | Fri Mar 12 11:20:00 GMT 2021
REPOSITORIES: MassIVE
Similar Datasets
Project description:Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-OMIC approach, here we identify the diverse metabolic programs operating in normal mammary populations. The proteomes of basal, luminal progenitor, and mature luminal cell populations revealed enrichment of glycolysis in basal cells and of oxidative phosphorylation in luminal progenitors. Single-cell transcriptomes corroborated lineage-specific metabolic identities and additional intra-lineage heterogeneity. Mitochondrial form-and-function differed across lineages, with clonogenicity correlating to mitochondrial activity. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed lineage-rooted metabolic vulnerabilities of mammary progenitors. Bioinformatics indicated breast cancer subtypes retain metabolic features of their putative cell-of-origin. Thus, lineage-rooted metabolic identities of normal mammary cells may underlie breast cancer metabolic heterogeneity and targeting these vulnerabilities could advance breast cancer therapy.
2021-04-28 | GSE168660 | GEO
Project description:Emerging data indicate that breast epithelial stem cells and progenitors, particularly those in the luminal epithelial cell lineage, are the cells-of-origin of breast carcinomas, and factors that influence breast cancer risk may alter the number and/or properties of these cells. We hypothesize that a subset of p27+ cells represent hormone-responsive progenitors that are quiescent due to the high activity of TGFβ signaling in these cells. The Estrogen-induced mammary tumor model in ACI inbred rats is physiologically relevant rodent model of breast cancer. In the present study we successfully generated Cdkn1b knockout ACI rats and performed comprehensive phenotypic assessment and RNAseq profiling using FACS sorted basal (CD24+CD29high) and luminal (CD24+CD29low) cell populations to characterize Cdkn1b+/+ and Cdkn1b-/- females in prepubertal and adult cohorts. We found that p27KO rats exhibited mammary differentiation phenotype and reduced numbers of mammary epithelial progenitor pool, Interestingly, p27 ablation has the most pronounced effect on luminal progenitor cell gene expression, and milk protein genes and pStat5 were dramatically upregulated, while PR and FoxA1 were greatly downregulated in Cdkn1b-/- luminal cells. Further characterization of mammary glands of prepubertal Cdkn1b knockout rats by fat pad transplantation illustrated p27 deletion in the mammary cancer susceptible ACI rat strain induced mammary epithelial cell differentiation through cell non-autonomous mechanisms.
2019-02-11 | GSE116831 | GEO
Project description:Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli – eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.
2021-09-22 | GSE184481 | GEO
Project description:To get molecular insight into age- and compartment-specific changes in telomere maintenance and associated properties in human mammary gland, we analyzed distinct subsets of normal human mammary epithelial cells. The cells were isolated by fluorescent activated cell sorting (FACS) directly from mammary tissue obtained from normal women undergoing reduction mammoplasties with concomitant removal of hematopoietic and endothelial cells by depletion of CD45pos and CD31pos cells. The three epithelial cell populations then isolated were: (i) CD49fhiEPCAMneg/low cells, (ii) CD49fposEPCAMpos cells and (iii) CD49fnegEPCAMpos cells. The CD49fhiEPCAM-/low cells are selectively enriched in mammary stem cells with functional mammary gland regenerating activity in suitably transplanted immunodeficient mice, bipotent progenitors that form colonies of adherent myoepithelial and luminal cells in vitro, myoepithelial-restricted progenitors that form colonies of exclusively adherent myoepithelial cells in vitro, and mature myoepithelial cells that are not clonogenic (collectively referred to as basal cells, BCs). The CD49fposEPCAMpos cells are selectively enriched in luminal progenitors (referred to as luminal progenitors, LPs); and the CD49fnegEPCAMpos cells are selectively enriched in mature luminal cells (referred to as luminal cells, LCs). Differences in gene expression in general and telomere associated genes in particular were elucidated by analyzing mammary epithelial subpopulations. Total RNA was isolated from 24 samples obtained from FACS purification of mammary epithelial subpopulations from 9 reduction mammoplasty breast tissues. Global gene expression profiling was performed by array.
2013-07-26 | E-GEOD-37223 | biostudies-arrayexpress
Project description:BRCA2 mutation carriers preferentially develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that Brca2mut/WT mammary organoids subjected to replication stress activated a transcriptional response that selectively expands Brca2mut/WT luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses revealed comparable epithelial compositions among wildtype and Brca2mut/WT mammary glands, Brca2mut/WT HR- luminal cells exhibited greater organoid formation and preferentially survived and expanded under replication stress. ScRNA-seq analysis corroborated the expansion of HR- luminal cells which express elevated levels of Tetraspanin-8 (Tspan8) and Thrsp mRNA, and pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevented Brca2mut/WT HR- luminal cell expansion. Our findings indicate that Brca2mut/WT cells have an activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.
2023-08-08 | GSE214539 | GEO
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
Project description:Aged STAT1-/- female mice spontaneously develop ERa+ PR+ mammary tumors that exhibit strikingly similar hormone-sensitivity and -dependency as human ERa+ luminal breast cancers. We used microarray data to compare the genetic relationships between the STAT1-/- mammary tumors and human breast cancers.
2011-12-15 | GSE31942 | GEO
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.
2012-10-11 | GSE35399 | GEO
Project description:The mammary epithlium goes through the drastic reorganization during development, pregnancy, and menopause as well as by external hormones and its mimicry, which risks the gland for the specific type of breast cancer. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary gland tissue was affected by 17β-estradiol (E2), progesterone (P4) and polybrominated diphenyl ethers (PBDEs). Then, we integrated the transcriptomes of 50K mouse and 24K human mammary epithelial cells from five different datasets and four individuals obtained by single-cell RNA sequencing (scRNAseq). The results indicated a putative trajectory originating from the embryonic mammary stem cells and differentiating into the three different epithelial lineage (Basal, Luminal alveolar, and Luminal hormone sensing) that were presumably sustained by unipotent progenitors in the postnatal glands. The identified lineage-specific gene sets inferred cells of origin of breast cancer using The Cancer Genome Atlas data and scRNAseq of human breast cancer. The comprehensive mammary cell atlas presented novel insights into the impact of the internal and external stimulati on the mammary epithelium in an unprecedented resolution.
2021-03-18 | GSE149949 | GEO
Project description:Aged STAT1-/- female mice spontaneously develop ERa+ PR+ mammary tumors that exhibit strikingly similar hormone-sensitivity and -dependency as human ERa+ luminal breast cancers. We used microarray data to compare the genetic relationships between the STAT1-/- mammary tumors and human breast cancers. We compared five STAT1-/- mammary tumor datasets with the publicaly available datasets of human breast cancers and those from other mouse mammary tumor models.
2011-12-15 | E-GEOD-31942 | biostudies-arrayexpress