Mammary epithelial stem cells

It has recently been shown that the progeny from a single cell may comprise the epithelial population of a fully developed lactating mammary outgrowth in mice. Serial transplantation of epithelial fragments from this clonally derived gland demonstrates that the subsequently generated outgrowths are also comprised of progeny from the original antecedent. All epithelial cell types were found to be present within these clonal normal populations including luminal, myoepithelial, ductal, and lobule‐committed epithelial progenitors and fully competent mammary epithelial stem cells. These observations demonstrate the presence of multipotent tissue‐specific epithelial stem cells among the parenchyma of the murine mammary gland. Similarly, genetic analysis of contiguous portions of individual human mammary ducts within the same breast indicates their clonal derivation. Here, we discuss the properties, location, division‐potential, senescence, and plasticity associated with mammary epithelial stem cells and present the developing evidence for their presence in human breast and their important role in the risk for breast cancer development. Further, we review the present morphologic and genetic evidence for the characterization of specific stem cell markers and lineage‐limited progenitor cells in human and rodent mammary epithelium. Microsc. Res. Tech. 52:190–203, 2001. Published 2001 Wiley‐Liss, Inc.

[1]  H. Smith,et al.  Contiguous patches of normal human mammary epithelium derived from a single stem cell: implications for breast carcinogenesis. , 1996, Cancer research.

[2]  M. Bissell,et al.  Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. , 1999, Developmental biology.

[3]  D. Medina,et al.  Evidence of separate pathways for viral and chemical carcinogenesis in c3h/stwi mouse mammary glands , 1980, International journal of cancer.

[4]  A. Spradling,et al.  Stem cells find their niche , 2001, Nature.

[5]  C. Cepko,et al.  Lineage-independent determination of cell type in the embryonic mouse retina , 1990, Neuron.

[6]  G. Smith,et al.  Unconventional application of standard light and electron immunocytochemical analysis to aldehyde-fixed, araldite-embedded tissues. , 1982, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[7]  R. Cardiff,et al.  Cultured mouse mammary epithelial cells: normal phenotype after implantation. , 1987, Journal of the National Cancer Institute.

[8]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[9]  David J. Anderson,et al.  Regulatory Mechanisms in Stem Cell Biology , 1997, Cell.

[10]  R. McKay,et al.  Stem Cells in the Central Nervous System , 1997, Science.

[11]  G. Smith,et al.  Dissociation of cytological and functional differential in virgin mouse mammary gland during inhibition of DNA synthesis. , 1982, Journal of cell science.

[12]  M. A. Tanner,et al.  Kinetics of mammary clonogenic cells and rat mammary cancer induction by X-rays or fission neutrons. , 1999, Journal of radiation research.

[13]  B. Gusterson,et al.  Differentiation of normal and malignant human squamous epithelium in vivo and in vitro: a morphologic study. , 1984, Ultrastructural pathology.

[14]  D. Medina,et al.  Hormones, chemicals and proviral gene expression as contributing factors during mammary carcinogenesis in C3H/StWi mice , 1981, International journal of cancer.

[15]  C. Potten,et al.  Stem cells: the intestinal stem cell as a paradigm. , 2000, Carcinogenesis.

[16]  Constance L. Cepko,et al.  A common progenitor for neurons and glia persists in rat retina late in development , 1987, Nature.

[17]  C. Welsch,et al.  Transplantation of human breast epithelia to mammary‐gland‐free fat‐pads of athymic nude mice: Influence of mammotrophic hormones on growth of breast epithelia , 1988, International journal of cancer.

[18]  G. Smith,et al.  An entire functional mammary gland may comprise the progeny from a single cell. , 1998, Development.

[19]  M. Emura.  Stem cells of the respiratory epithelium and their in vitro cultivation , 1997, In Vitro Cellular & Developmental Biology - Animal.

[20]  B. Mintz,et al.  Gene control of neoplasia. I. Genotypic mosaicism in normal and preneoplastic mammary glands of allophenic mice. , 1969, Journal of the National Cancer Institute.

[21]  Fiona M. Watt,et al.  Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression , 1993, Cell.

[22]  R. Callahan,et al.  MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways , 2000, Oncogene.

[23]  C. Boulanger,et al.  Mammary stem cell repertoire: new insights in aging epithelial populations , 2002, Mechanisms of Ageing and Development.

[24]  L. Young,et al.  The influence of mammogenic hormones on serially transplanted mouse mammary gland. , 1971, Experimental gerontology.

[25]  G H Smith,et al.  Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. , 1997, Tissue & cell.

[26]  F. Kittrell,et al.  Properties of mouse mammary epithelial cell lines characterized by in vivo transplantation and in vitro immunocytochemical methods. , 1986, Journal of the National Cancer Institute.

[27]  F. Kittrell,et al.  Development of mammary preneoplasias in vivo from mouse mammary epithelial cell lines in vitro. , 1992, Cancer research.

[28]  D. Medina,et al.  Chemical carcinogen-induced tumorigenesis in parous, involuted mouse mammary glands. , 1999, Journal of the National Cancer Institute.

[29]  G. Cunha,et al.  Transplanted mammary epithelium grows in association with host stroma: Aging of serially transplanted mammary gland is intrinsic to epithelial cells , 1983, Mechanisms of Ageing and Development.

[30]  J. Williams,et al.  Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. , 1983, Developmental biology.

[31]  W. R. Lyons.  Hormonal synergism in mammary growth , 1958, Proceedings of the Royal Society of London. Series B - Biological Sciences.

[32]  C. Welsch,et al.  Normal but not carcinomatous primary rat mammary epithelium: readily transplanted to and maintained in the athymic nude mouse. , 1987, Journal of the National Cancer Institute.

[33]  A. Rimm,et al.  TRANSPLANTATION OF HEMATOPOIETIC AND LYMPHOID CELLS IN MICE: H‐2 MATCHED UNRELATED ADULT DONORS COMPARED WITH H‐2 MISMATCHED FETAL DONORS , 1976, Transplantation.

[34]  P. Jones.  Epithelial stem cells , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[35]  Fiona M Watt,et al.  c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny , 2001, Current Biology.

[36]  Y. Sonoda,et al.  Human cord blood-derived primitive progenitors are enriched in CD34+c-kit− cells: correlation between long-term culture-initiating cells and telomerase expression , 1998, Leukemia.

[37]  D. Roop,et al.  Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[38]  R. Guzman,et al.  Effect of parity on recovery of inapparent nodule-transformed mammary gland cells in vivo. , 1978, Cancer research.

[39]  B. O’Malley,et al.  Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. , 1998, Carcinogenesis.

[40]  M. Stratton,et al.  Genetic alterations in ‘normal’ luminal and myoepithelial cells of the breast , 1999, The Journal of pathology.

[41]  D. Medina,et al.  A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. , 1988, Journal of cell science.

[42]  D. Medina,et al.  Expression of pregnancy-specific genes in preneoplastic mouse mammary tissues from virgin mice. , 1984, Cancer research.

[43]  M. O'hare,et al.  Clonal characterization of mouse mammary luminal epithelial and myoepithelial cells separated by fluorescence-activated cell sorting , 1998, In Vitro Cellular & Developmental Biology - Animal.

[44]  L. Hennighausen,et al.  Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population. , 1995, Developmental biology.

[45]  Mina J Bissell,et al.  Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. , 2002, Genes & development.

[46]  T. Graubert,et al.  Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. , 2002, Developmental biology.

[47]  L. Hennighausen,et al.  An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. , 2002, Development.

[48]  D. Medina,et al.  Unlimited division potential of precancerous mouse mammary cells after spontaneous or carcinogen-induced transformation. , 1975, Federation proceedings.

[49]  D. Medina,et al.  Increased concentration of an indigenous proviral mouse mammary tumor virus long terminal repeat-containing transcript is associated with neoplastic transformation of mammary epithelium in C3H/Sm mice , 1984, Journal of virology.

[50]  R. Hill,et al.  An electron microscope study of the internal structure of casein micelles , 1964, Journal of Dairy Research.

[51]  F. Kittrell,et al.  Immortalization phenotype dissociated from the preneoplastic phenotype in mouse mammary epithelial outgrowths in vivo. , 1993, Carcinogenesis.

[52]  Expansion in vitro of retrovirally marked totipotent hematopoietic stem cells. , 1990 .

[53]  H. Sang U,et al.  Cell type-specific development of rodent central nervous system progenitor cells in culture. , 1998, Journal of neurosurgery.

[54]  H. Tucker,et al.  Estimates of parenchymal, stromal, and lymph node deoxyribonucleic acid in mammary glands of C3H/Crgl-2 mice. , 1965, Life sciences.

[55]  G. Smith,et al.  Functional differentiation in mouse mammary gland epithelium is attained through DNA synthesis, inconsequent of mitosis. , 1981, Developmental biology.

[56]  L. Young,et al.  The influence of host and tissue age on life span and growth rate of serially transplanted mouse mammary gland. , 1971, Experimental gerontology.

[57]  D. Medina,et al.  Chemical carcinogenesis in C3H/StWi mice, a worthwhile experimental model for breast cancer. , 1978, Cancer research.

[58]  R. Cardiff,et al.  Mammary Disease Mice Model Premalignant Polyoma Middle-T Transgenic Updated Version , 2001 .

[59]  C. Boulanger,et al.  Reducing mammary cancer risk through premature stem cell senescence , 2001, Oncogene.

[60]  S. Levison,et al.  Multipotential and lineage restricted precursors coexist in the mammalian perinatal subventricular zone , 1997, Journal of neuroscience research.

[61]  R. Weinberg,et al.  A paracrine role for the epithelial progesterone receptor in mammary gland development. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[62]  H. Traurig,et al.  A radioautographic study of cell proliferation in the mammary gland of the pregnant mouse , 1967, The Anatomical record.

[63]  D. Faller,et al.  Microsatellite alterations indicating monoclonality in atypical hyperplasias associated with breast cancer. , 1997, Human pathology.

[64]  L. Young,et al.  Influence of cell division on an aging process. Life span of mouse mammary epithelium during serial propagation in vivo. , 1971, Experimental Cell Research.

[65]  C. Eaves,et al.  Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. , 1998, Differentiation; research in biological diversity.

[66]  R. Guzman,et al.  Detection of inapparent nodule-transformed cells in the mammary gland tissues of virgin female BALB/cfC3H mice. , 1978, Cancer research.

[67]  F. Kittrell,et al.  Morphological and functional properties of TM preneoplastic mammary outgrowths. , 1993, Cancer research.

[68]  D. Medina.  Biological and molecular characteristics of the premalignant mouse mammary gland. , 2002, Biochimica et biophysica acta.

[69]  Y. Sonoda,et al.  Haematopoietic action of flt3 ligand on cord blood‐derived CD34‐positive cells expressing different levels of flt3 or c‐kit tyrosine kinase receptor: comparison with stem cell factor , 1998, European journal of haematology.

[70]  Gilbert H. Smith,et al.  Putative epithelial stem cell loss corresponds with mammary growth senescence , 2002, Cell and Tissue Research.

[71]  L. Hayflick.  Aging, longevity, and immortality in vitro , 1992, Experimental Gerontology.

[72]  A. Thor,et al.  Loss of Heterozygosity in Normal Tissue Adjacent to Breast Carcinomas , 1996, Science.

[73]  K. Deome,et al.  Growth of Mouse Mammary Glands in vivo after Monolayer Culture , 1965, Science.

[74]  Gilbert H. Smith.  Functional differentiation of virgin mouse mammary epithelium in explant culture is dependent upon extracellular proline , 1987, Journal of cellular physiology.

[75]  K. Kamiya,et al.  Quantitative Studies of Ductal Versus Alveolar Differentiation from Rat Mammary Clonogens , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[76]  C. Cepko,et al.  Multipotent neural cell lines can engraft and participate in development of mouse cerebellum , 1992, Cell.

[77]  M. Stratton,et al.  Detection of allelic imbalance indicates that a proportion of mammary hyperplasia of usual type are clonal, neoplastic proliferations. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[78]  C. Tickle,et al.  Lumen formation in the developing mouse mammary gland. , 1983, Journal of embryology and experimental morphology.

[79]  M. O'hare,et al.  Differentiation of Separated Mouse Mammary Luminal Epithelial and Myoepithelial Cells Cultured on EHS Matrix Analyzed by Indirect Immunofluorescence of Cytoskeletal Antigens , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[80]  H. Bern,et al.  Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. , 1959, Cancer research.

[81]  J. Heddle,et al.  The relationships among stem cells, crypts, and villi in the small intestine of mice as determined by mutation tagging , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[82]  D. Medina,et al.  Mammary noduligenesis and tumorigenesis in pathogen-free C3Hf mice. , 1973, Journal of the National Cancer Institute.

[83]  W. Carter,et al.  Distinct functions for integrins alpha 3 beta 1 in focal adhesions and alpha 6 beta 4/bullous pemphigoid antigen in a new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes , 1990, The Journal of cell biology.

[84]  N. Zeps,et al.  Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth. , 1998, Differentiation; research in biological diversity.

[85]  N. D. Kim,et al.  Characterization of rat mammary epithelial cell subpopulations by peanut lectin and anti-Thy-1.1 antibody and study of flow-sorted cells in vivo. , 1993, Experimental cell research.

[86]  J. T. Young,et al.  The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study. , 1968, Proceedings of the National Academy of Sciences of the United States of America.

[87]  F. Kittrell,et al.  Biological and genetic properties of the p53 null preneoplastic mammary epithelium , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Science.

[89]  B. O’Malley,et al.  p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[90]  L. Faulkin,et al.  Regulation of growth and spacing of gland elements in the mammary fat pad of the C3H mouse. , 1960, Journal of the National Cancer Institute.

[91]  D. Gallahan,et al.  Long-term in vivo expression of genes introduced by retrovirus-mediated transfer into mammary epithelial cells , 1991, Journal of virology.