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John J. Wysolmerski - One of the best experts on this subject based on the ideXlab platform.
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parathyroid hormone related protein is not required for normal ductal or alveolar Development in the post natal Mammary gland
PLOS ONE, 2011Co-Authors: Kata Borasgranic, Minoti Hiremath, Joshua Vanhouten, John J. WysolmerskiAbstract:PTHrP is necessary for the formation of the embryonic Mammary gland and, in its absence, the embryonic Mammary bud fails to form the neonatal duct system. In addition, PTHrP is produced by the breast during lactation and contributes to the regulation of maternal calcium homeostasis during milk production. In this study, we examined the role of PTHrP during post-natal Mammary Development. Using a PTHrP-lacZ transgenic mouse, we surveyed the expression of PTHrP in the developing post-natal mouse Mammary gland. We found that PTHrP expression is restricted to the basal cells of the gland during pubertal Development and becomes expressed in milk secreting alveolar cells during pregnancy and lactation. Based on the previous findings that overexpression of PTHrP in cap and myoepithelial cells inhibited ductal elongation during puberty, we predicted that ablation of native PTHrP expression in the post-natal gland would result in accelerated ductal Development. To address this hypothesis, we generated two conditional models of PTHrP-deficiency specifically targeted to the postnatal Mammary gland. We used the MMTV-Cre transgene to ablate the floxed PTHrP gene in both luminal and myoepithelial cells and a tetracycline-regulated K14-tTA;tetO-Cre transgene to target PTHrP expression in just myoepithelial and cap cells. In both models of PTHrP ablation, we found that Mammary Development proceeds normally despite the absence of PTHrP. We conclude that PTHrP signaling is not required for normal ductal or alveolar Development.
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molecular mechanisms guiding embryonic Mammary gland Development
Cold Spring Harbor Perspectives in Biology, 2010Co-Authors: Pamela Cowin, John J. WysolmerskiAbstract:The Mammary gland is an epidermal appendage that begins to form during embryogenesis, but whose Development is only completed during pregnancy. Each Mammary gland begins as a budlike invagination of the surface ectoderm, which then gives rise to a simple duct system by birth. Subsequent Development occurs during sexual maturation and during pregnancy and lactation. In this review, we outline the distinct stages of embryonic Mammary Development and discuss the molecular pathways involved in the regulation of morphogenesis at each stage. We also discuss the potential relevance of embryonic breast Development to the pathophysiology of breast cancer and highlight questions for future research.
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Characterization of the Six1 homeobox gene in normal Mammary gland morphogenesis.
BMC Developmental Biology, 2010Co-Authors: Ricardo D. Coletta, John J. Wysolmerski, Erica L. Mccoy, Valerie Burns, Kiyoshi Kawakami, James L. Mcmanaman, Heide L. FordAbstract:Background The Six1 homeobox gene is highly expressed in the embryonic Mammary gland, continues to be expressed in early postnatal Mammary Development, but is lost when the Mammary gland differentiates during pregnancy. However, Six1 is re-expressed in breast cancers, suggesting that its re-instatement in the adult Mammary gland may contribute to breast tumorigenesis via initiating a Developmental process out of context. Indeed, recent studies demonstrate that Six1 overexpression in the adult mouse Mammary gland is sufficient for initiating invasive carcinomas, and that its overexpression in xenograft models of Mammary cancer leads to metastasis. These data demonstrate that Six1 is causally involved in both breast tumorigenesis and metastasis, thus raising the possibility that it may be a viable therapeutic target. However, because Six1 is highly expressed in the developing Mammary gland, and because it has been implicated in the expansion of Mammary stem cells, targeting Six1 as an anti-cancer therapy may have unwanted side effects in the breast.
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parathyroid hormone related protein a Developmental regulatory molecule necessary for Mammary gland Development
Journal of Mammary Gland Biology and Neoplasia, 1999Co-Authors: Maureen E Dunbar, John J. WysolmerskiAbstract:Parathyroid hormone-related protein (PTHrP) wasoriginally identified as the tumor factor responsiblefor a clinical syndrome known as humoral hypercalcemiaof malignancy. It is now appreciated that PTHrP3 is a Developmental regulatory moleculeexpressed during the formation of a wide variety oforgans. Recently, our laboratory has demonstrated thatPTHrP is necessary for Mammary gland Development. Ourstudies have suggested that this molecule participatesin the regulation of epithelial-mesenchymal interactionsduring embryonic Mammary Development and perhaps alsoduring adolescent ductal morphogenesis. In addition, it has been suggested that PTHrP plays acritical role in the establishment of bone metastases inbreast cancer. In this article, we will discuss thecurrent knowledge of the mechanisms underlying PTHrPs actions during normal Mammary Development andin breast cancer.
Zena Werb - One of the best experts on this subject based on the ideXlab platform.
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lgr5 expressing cells are sufficient and necessary for postnatal Mammary gland organogenesis
Cell Reports, 2013Co-Authors: Vicki Plaks, Audrey Brenot, Devon A Lawson, Jelena R Linnemann, Eline C Van Kappel, Karren C Wong, Frederic J De Sauvage, Ophir D Klein, Zena WerbAbstract:Summary Mammary epithelial stem cells are vital to tissue expansion and remodeling during various phases of postnatal Mammary Development. Basal Mammary epithelial cells are enriched in Wnt-responsive cells and can reconstitute cleared Mammary fat pads upon transplantation into mice. Lgr5 is a Wnt-regulated target gene and was identified as a major stem cell marker in the small intestine, colon, stomach, and hair follicle, as well as in kidney nephrons. Here, we demonstrate the outstanding regenerative potential of a rare population of Lgr5 -expressing ( Lgr5 + ) Mammary epithelial cells (MECs). We found that Lgr5 + cells reside within the basal population, are superior to other basal cells in regenerating functional Mammary glands (MGs), are exceptionally efficient in reconstituting MGs from single cells, and exhibit regenerative capacity in serial transplantations. Loss-of-function and depletion experiments of Lgr5 + cells from transplanted MECs or from pubertal MGs revealed that these cells are not only sufficient but also necessary for postnatal Mammary organogenesis.
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gata3 in Development and cancer differentiation cells gata have it
Journal of Cellular Physiology, 2010Co-Authors: Jonathan Chou, Sylvain Provot, Zena WerbAbstract:There is increasing evidence that the numerous mechanisms that regulate cell differentiation during normal Development are also involved in tumorigenesis. In breast cancer, differentiation markers expressed by the primary tumor are routinely profiled to guide clinical decisions. Indeed, numerous studies have shown that the differentiation profile correlates with the metastatic potential of tumors. The transcription factor GATA3 has emerged recently as a strong predictor of clinical outcome in human luminal breast cancer. In the Mammary gland, GATA3 is required for luminal epithelial cell differentiation and commitment, and its expression is progressively lost during luminal breast cancer progression as cancer cells acquire a stem cell-like phenotype. Importantly, expression of GATA3 in GATA3-negative, undifferentiated breast carcinoma cells is sufficient to induce tumor differentiation and inhibits tumor dissemination in a mouse model. These findings demonstrate the exquisite ability of a differentiation factor to affect malignant properties, and raise the possibility that GATA3 or its downstream genes could be used in treating luminal breast cancer. This review highlights our recent understanding of GATA3 in both normal Mammary Development and tumor differentiation.
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gata 3 maintains the differentiation of the luminal cell fate in the Mammary gland
Cell, 2006Co-Authors: Hosein Kourosmehr, Mark D Sternlicht, Euan M Slorach, Zena WerbAbstract:The GATA family of transcription factors plays fundamental roles in cell-fate specification. However, it is unclear if these genes are necessary for the maintenance of cellular differentiation after Development. We identified GATA-3 as the most highly enriched transcription factor in the Mammary epithelium of pubertal mice. GATA-3 was found in the luminal cells of Mammary ducts and the body cells of terminal end buds (TEBs). Upon conditional deletion of GATA-3, mice exhibited severe defects in Mammary Development due to failure in TEB formation during puberty. After acute GATA-3 loss, adult mice exhibited undifferentiated luminal cell expansion with basement-membrane detachment, which led to caspase-mediated cell death in the long term. Further, FOXA1 was identified as a downstream target of GATA-3 in the Mammary gland. This suggests that GATA-3 actively maintains luminal epithelial differentiation in the adult Mammary gland, which raises important implications for the pathogenesis of breast cancer.
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hormonal and local control of Mammary branching morphogenesis
Differentiation, 2006Co-Authors: Mark D Sternlicht, Hosein Kourosmehr, Zena WerbAbstract:Unlike other branched organs, the Mammary gland undergoes most of its branching during adolescent rather than embryonic Development. Its morphogenesis begins in utero, pauses between birth and puberty, and resumes in response to ovarian estrogens to form an open ductal tree that eventually fills the entire Mammary fat pad of the young female adult. Importantly, this "open" architecture leaves room during pregnancy for the organ to develop milk-producing alveoli like leaves on otherwise bare branches. Thereafter, the ducts serve to deliver the milk that is produced throughout lactation. The hormonal cues that elicit these various phases of Mammary Development utilize local signaling cascades and reciprocal stromal-epithelial interactions to orchestrate the tissue reorganization, differentiation and specific activities that define each phase. Fortunately, the Mammary gland is rather amenable to experimental inquiry and, as a result, we have a fair, although incomplete, understanding of the mechanisms that control its Development. This review discusses our current sense and understanding of those mechanisms as they pertain to Mammary branching, with the caveat that many more aspects are still waiting to be solved.
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stromal effects on Mammary gland Development and breast cancer
Science, 2002Co-Authors: Bryony S Wiseman, Zena WerbAbstract:Breast cancer manifests itself in the Mammary epithelium, yet there is a growing recognition that Mammary stromal cells also play an important role in tumorigenesis. During its Developmental cycle, the Mammary gland displays many of the properties associated with breast cancer, and many of the stromal factors necessary for Mammary Development also promote or protect against breast cancer. Here we review our present knowledge of the specific factors and cell types that contribute to epithelial-stromal crosstalk during Mammary Development. To find cures for diseases like breast cancer that rely on epithelial-stromal crosstalk, we must understand how these different cell types communicate with each other.
Justin A Colacino - One of the best experts on this subject based on the ideXlab platform.
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hybrid stem cell states insights into the relationship between Mammary Development and breast cancer using single cell transcriptomics
Frontiers in Cell and Developmental Biology, 2020Co-Authors: Tasha Thong, Max S Wicha, Yutong Wang, Michael D Brooks, Christopher T Lee, Clayton Scott, Laura Balzano, Justin A ColacinoAbstract:Similarities between stem cells and cancer cells have implicated a role for Mammary stem cells in breast carcinogenesis. Recent evidence suggests that normal breast stem cells exist in multiple phenotypic states: epithelial, mesenchymal, and hybrid epithelial/mesenchymal. The proportion of cells in these states vary between individuals, suggesting that state dynamics may be influenced by genetics or environment. Conditional reprogramming (CR), an in vitro method of expanding patient derived tissue samples, promotes the rapid induction of a stem-like state in the absence of genetic manipulation. The goal of this study was to use single-cell RNA sequencing to quantify the cell state distributions of normal human Mammary (NM) cells isolated from patients undergoing voluntary reduction mammoplasty (n=3) before and after CR, investigating stem cell populations, and identifying gene and pathway drivers of stem cell phenotypes. Unbiased clustering revealed that post-CR, myoepithelial and luminal cell populations are retained, while fibroblast, endothelial, and immune cell populations are depleted. Compared to NM cells, CR cells show higher expression of an embryonic stem cell gene signature and differentially express stem cell and cancer related genes (LGALS1, SKA2, MKI67, HJURP, BIRC5, CCNB1, and BUB1). Pseudotime analysis and alignment to a mouse single-cell transcriptome atlas spanning Mammary gland Development revealed that NM cells align most closely to adult mouse cells and CR cells align across the trajectory with a population aligning to the embryonic mouse cells. We identified the emergence of three hybrid populations, a KRT14+/KRT18+ population (L/B), consistent with luminal progenitor cells, an EPCAM+/VIM+ (E/M) population, associated with cells undergoing the epithelial to mesenchymal transition, and a quadruple positive hybrid population, expressing all four markers. Pseudotime analysis and alignment to the mouse Developmental trajectory revealed that E/M hybrids are the most Developmentally immature, aligning along both luminal and basal Developmental trajectories. Finally, pseudotime analysis and alignment of bulk breast tumors from the cancer genome atlas (TCGA), revealed that breast cancer subtypes express distinct Developmental signatures, with basal tumors expressing the most “Developmentally immature” phenotype. These results highlight phenotypic plasticity of normal Mammary stem cells and provide insight into the relationship between hybrid cell populations, stemness, and cancer.
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hybrid stem cell states insights into the relationship between Mammary Development and breast cancer using single cell transcriptomics
Frontiers in Cell and Developmental Biology, 2020Co-Authors: Tasha Thong, Max S Wicha, Yutong Wang, Michael D Brooks, Christopher T Lee, Clayton Scott, Laura Balzano, Justin A ColacinoAbstract:Similarities between stem cells and cancer cells have implicated Mammary stem cells in breast carcinogenesis. Recent evidence suggests that normal breast stem cells exist in multiple phenotypic states: epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M). Hybrid E/M cells in particular have been implicated in breast cancer metastasis and poor prognosis. Mounting evidence also suggests that stem cell phenotypes change throughout the life course, for example, through embryonic Development and pregnancy. The goal of this study was to use single cell RNA-sequencing to quantify cell state distributions of the normal Mammary (NM) gland throughout Developmental stages and when perturbed into a stem-like state in vitro using conditional reprogramming (CR). Using machine learning based dataset alignment, we integrate multiple Mammary gland single cell RNA-seq datasets from human and mouse, along with bulk RNA-seq data from breast tumors in the Cancer Genome Atlas (TCGA), to interrogate hybrid stem cell states in the normal Mammary gland and cancer. CR of human Mammary cells induces an expanded stem cell state, characterized by increased expression of embryonic stem cell associated genes. Alignment to a mouse single-cell transcriptome atlas spanning Mammary gland Development from in utero to adulthood revealed that NM cells align to adult mouse cells and CR cells align across the pseudotime trajectory with a stem-like population aligning to the embryonic mouse cells. Three hybrid populations emerge after CR that are rare in NM: KRT18+/KRT14+ (hybrid luminal/basal), EPCAM+/VIM+ (hybrid E/M), and a quadruple positive population, expressing all four markers. Pseudotime analysis and alignment to the mouse Developmental trajectory revealed that E/M hybrids are the most Developmentally immature. Analyses of single cell mouse Mammary RNA-seq throughout pregnancy show that during gestation, there is an enrichment of hybrid E/M cells, suggesting that these cells play an important role in Mammary morphogenesis during lactation. Finally, pseudotime analysis and alignment of TCGA breast cancer expression data revealed that breast cancer subtypes express distinct Developmental signatures, with basal tumors representing the most "Developmentally immature" phenotype. These results highlight phenotypic plasticity of normal Mammary stem cells and provide insight into the relationship between hybrid cell populations, stemness, and cancer.
Geoffrey M Wahl - One of the best experts on this subject based on the ideXlab platform.
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single cell chromatin analysis of Mammary gland Development reveals cell state transcriptional regulators and lineage relationships
Cell Reports, 2019Co-Authors: Chiyeh Chung, Christopher Dravis, Sebastian Preissl, Olivier Poirion, Gidsela Luna, Xiaomeng Hou, Rajshekhar R Giraddi, Bing Ren, Geoffrey M WahlAbstract:Technological improvements enable single-cell epigenetic analyses of organ Development. We reasoned that high-resolution single-cell chromatin accessibility mapping would provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal Mammary gland Development. Here, we provide a single-cell resource of chromatin accessibility for murine Mammary Development from the peak of fetal Mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity. The ability of single-cell chromatin profiling to separate E18 fetal Mammary cells into clusters exhibiting basal-like and luminal-like chromatin features is noteworthy. Such distinctions were not evident in analyses of droplet-based single-cell transcriptomic data. We present a web application as a scientific resource for facilitating future analyses of the gene regulatory networks involved in Mammary Development.
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single cell chromatin accessibility analysis of Mammary gland Development reveals cell state transcriptional regulators and cellular lineage relationships
bioRxiv, 2019Co-Authors: Chiyeh Chung, Christopher Dravis, Sebastian Preissl, Olivier Poirion, Gidsela Luna, Xiaomeng Hou, Rajshekhar R Giraddi, Bing Ren, Geoffrey M WahlAbstract:Summary It has only recently become possible to obtain single-cell level resolution of the epigenetic changes that occur during organ Development. We reasoned that precision single-cell chromatin accessibility mapping of Mammary gland Development could provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal Mammary gland Development. Here, we provide the first single-cell resource of chromatin accessibility for murine Mammary Development from the peak of fetal Mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity, and we present a web application as a scientific resource for facilitating future analyses. Strikingly, these single-cell chromatin profiling data reveal that fMaSCs can be separated into basal-like and luminal-like lineages, providing evidence of early lineage segregation prior to birth. Such distinctions were not evident in analyses of single-cell transcriptomic data.
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epigenetic and transcriptomic profiling of Mammary gland Development and tumor models disclose regulators of cell state plasticity
Cancer Cell, 2018Co-Authors: Christopher Dravis, Chiyeh Chung, Gidsela Luna, Nikki K Lytle, Jaslem Herreravaldez, Christy L Trejo, Tannishtha Reya, Geoffrey M WahlAbstract:Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during Mammary Development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.
Chiyeh Chung - One of the best experts on this subject based on the ideXlab platform.
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single cell chromatin analysis of Mammary gland Development reveals cell state transcriptional regulators and lineage relationships
Cell Reports, 2019Co-Authors: Chiyeh Chung, Christopher Dravis, Sebastian Preissl, Olivier Poirion, Gidsela Luna, Xiaomeng Hou, Rajshekhar R Giraddi, Bing Ren, Geoffrey M WahlAbstract:Technological improvements enable single-cell epigenetic analyses of organ Development. We reasoned that high-resolution single-cell chromatin accessibility mapping would provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal Mammary gland Development. Here, we provide a single-cell resource of chromatin accessibility for murine Mammary Development from the peak of fetal Mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity. The ability of single-cell chromatin profiling to separate E18 fetal Mammary cells into clusters exhibiting basal-like and luminal-like chromatin features is noteworthy. Such distinctions were not evident in analyses of droplet-based single-cell transcriptomic data. We present a web application as a scientific resource for facilitating future analyses of the gene regulatory networks involved in Mammary Development.
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single cell chromatin accessibility analysis of Mammary gland Development reveals cell state transcriptional regulators and cellular lineage relationships
bioRxiv, 2019Co-Authors: Chiyeh Chung, Christopher Dravis, Sebastian Preissl, Olivier Poirion, Gidsela Luna, Xiaomeng Hou, Rajshekhar R Giraddi, Bing Ren, Geoffrey M WahlAbstract:Summary It has only recently become possible to obtain single-cell level resolution of the epigenetic changes that occur during organ Development. We reasoned that precision single-cell chromatin accessibility mapping of Mammary gland Development could provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal Mammary gland Development. Here, we provide the first single-cell resource of chromatin accessibility for murine Mammary Development from the peak of fetal Mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity, and we present a web application as a scientific resource for facilitating future analyses. Strikingly, these single-cell chromatin profiling data reveal that fMaSCs can be separated into basal-like and luminal-like lineages, providing evidence of early lineage segregation prior to birth. Such distinctions were not evident in analyses of single-cell transcriptomic data.
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epigenetic and transcriptomic profiling of Mammary gland Development and tumor models disclose regulators of cell state plasticity
Cancer Cell, 2018Co-Authors: Christopher Dravis, Chiyeh Chung, Gidsela Luna, Nikki K Lytle, Jaslem Herreravaldez, Christy L Trejo, Tannishtha Reya, Geoffrey M WahlAbstract:Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during Mammary Development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.
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single cell transcriptomes distinguish stem cell state changes and lineage specification programs in early Mammary gland Development
Cell Reports, 2018Co-Authors: Rajshekhar R Giraddi, Chiyeh Chung, Christopher Dravis, Christy L Trejo, Richard E Heinz, Ozlen Balcioglu, Mark Novotny, Berhane M Hagos, Elnaz Mirzaei Mehrabad, Luo Wei RodewaldAbstract:Summary The Mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge of Developmental kinetics and mechanisms of lineage specification is lacking. We address this significant knowledge gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, and adult mouse Mammary Development. From these data, we map the chronology of transcriptionally and epigenetically distinct cell states and distinguish fetal Mammary stem cells (fMaSCs) from their precursors and progeny. fMaSCs show balanced co-expression of factors associated with discrete adult lineages and a metabolic gene signature that subsides during maturation but reemerges in some human breast cancers and metastases. These data provide a useful resource for illuminating Mammary cell heterogeneity, the kinetics of differentiation, and Developmental correlates of tumorigenesis.
