Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JEGeneration of a functional mammary gland from a single stem cell. Nature 439: 84-88

Royal Melbourne Hospital, Melbourne, Victoria, Australia
Nature (Impact Factor: 41.46). 02/2006; 439(7072):84-8. DOI: 10.1038/nature04372
Source: PubMed


The existence of mammary stem cells (MaSCs) has been postulated from evidence that the mammary gland can be regenerated by transplantation of epithelial fragments in mice. Interest in MaSCs has been further stimulated by their potential role in breast tumorigenesis. However, the identity and purification of MaSCs has proved elusive owing to the lack of defined markers. We isolated discrete populations of mouse mammary cells on the basis of cell-surface markers and identified a subpopulation (Lin-CD29hiCD24+) that is highly enriched for MaSCs by transplantation. Here we show that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo. The transplanted cell contributed to both the luminal and myoepithelial lineages and generated functional lobuloalveolar units during pregnancy. The self-renewing capacity of these cells was demonstrated by serial transplantation of clonal outgrowths. In support of a potential role for MaSCs in breast cancer, the stem-cell-enriched subpopulation was expanded in premalignant mammary tissue from MMTV-wnt-1 mice and contained a higher number of MaSCs. Our data establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.


Available from: Mark J Shackleton, Jun 24, 2014
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    • "The cycling and quiescence of MaSCs has been especially difficult to study (Visvader and Stingl, 2014). It has been shown that long-lived, label-retaining cells are enriched in the MaSC/basal compartment, indicating they are slowly dividing (Shackleton et al., 2006). However, it is still unclear how DNA damage affects the cycling and quiescence properties of MaSCs. "
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    ABSTRACT: Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 08/2015; 5(3). DOI:10.1016/j.stemcr.2015.07.009 · 5.37 Impact Factor
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    • "These processes are likely supported by a population of mammary stem cells that resides within the tissue. Regeneration of the entire gland from one single cell in multiple passages together with lineage-tracing experiments in vivo constitute compelling evidence for the existence of stem cell populations in the mouse mammary gland (Prater et al., 2014; Rios et al., 2014; Shackleton et al., 2006). However, owing to obvious experimental limitations, there is no direct definitive proof for the existence of a bona fide stem cell population active in the adult human mammary gland. "
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    ABSTRACT: Characterization of normal breast stem cells is important for understanding their role in breast development and in breast cancer. However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known. In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals. Comparing predictions of these models with immunohistochemical analysis of tissue sections for candidate stem cell markers, we defined distinct areas where stem cells reside in the mammary lobule. An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of nulliparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 03/2015; 4(4). DOI:10.1016/j.stemcr.2015.02.013 · 5.37 Impact Factor
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    • "We first demonstrated that LBH is predominantly expressed, with a nuclear-specific pattern, in the regenerative basal epithelium of both mouse and human mammary glands, including in WNTresponsive Lgr5 + MaSCs. By contrast, LBH was not or was only barely expressed in luminal cells, which lack regenerative capacity in transplantation assays (Shackleton et al., 2006; Stingl et al., 2006) and multi-lineage differentiation potential in situ (van Amerongen et al., 2012; Van Keymeulen et al., 2011). "
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    ABSTRACT: The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(5). DOI:10.1242/dev.110403 · 6.46 Impact Factor
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