Home LiteratureArticle Details
PMID: 19933147 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis.

Genes & development ·Vol. 23 ·No. 22 ·2009-11-15 ·Pages 2563-77

Visvader JE

Abstract

The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarchy. Potential relationships between normal epithelial populations and breast tumor subtypes are discussed, with implications for understanding the cellular etiology underpinning breast tumor heterogeneity.

MeSH Terms
Animals Breast Neoplasms/genetics,pathology,physiopathology Cell Differentiation Female Gene Expression Regulation Humans Mammary Glands, Animal/cytology,pathology,transplantation Mammary Glands, Human/cytology,pathology Mutation/genetics Pregnancy Stem Cells/cytology Ubiquitin-Protein Ligases/genetics Wnt Proteins/metabolism
Chemicals
Wnt Proteins BRAP protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Visvader Jane E
VBCRC (Victorian Breast Cancer Research Consortium) Laboratory, The Walter and Eliza Hall of Medical Research, Parkville, Victoria 3052, Australia. [email protected]
References (121)
121 references, click to expand
  1. Loss of heterozygosity in normal tissue adjacent to breast carcinomas.
    Science. 1996 Dec 20;274(5295):2057-9 PMID: 8953032
  2. The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study.
    Proc Natl Acad Sci U S A. 1968 Sep;61(1):53-60 PMID: 4301594
  3. CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis.
    Cancer Cell. 2009 May 5;15(5):389-401 PMID: 19411068
  4. Modifiers of risk of hereditary breast cancer.
    Oncogene. 2006 Sep 25;25(43):5832-6 PMID: 16998497
  5. PML depletion disrupts normal mammary gland development and skews the composition of the mammary luminal cell progenitor pool.
    Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4725-30 PMID: 19261859
  6. BRCA1 functions as a breast stem cell regulator.
    J Med Genet. 2004 Jan;41(1):1-5 PMID: 14729816
  7. Evidence for a stem cell hierarchy in the adult human breast.
    J Cell Biol. 2007 Apr 9;177(1):87-101 PMID: 17420292
  8. Efficient tumour formation by single human melanoma cells.
    Nature. 2008 Dec 4;456(7222):593-8 PMID: 19052619
  9. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation.
    Nat Genet. 1999 May;22(1):37-43 PMID: 10319859
  10. Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia.
    Development. 2005 Jan;132(2):267-77 PMID: 15590737
  11. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.
    PLoS Biol. 2009 Jun 2;7(6):e1000121 PMID: 19492080
  12. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2196-201 PMID: 16452162
  13. Aberrant activation of notch signaling in human breast cancer.
    Cancer Res. 2006 Feb 1;66(3):1517-25 PMID: 16452208
  14. Contiguous patches of normal human mammary epithelium derived from a single stem cell: implications for breast carcinogenesis.
    Cancer Res. 1996 Jan 15;56(2):402-4 PMID: 8542598
  15. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
    Science. 1987 Jan 9;235(4785):177-82 PMID: 3798106
  16. Transient increase in the risk of breast cancer after giving birth.
    N Engl J Med. 1994 Jul 7;331(1):5-9 PMID: 8202106
  17. Information networks in the mammary gland.
    Nat Rev Mol Cell Biol. 2005 Sep;6(9):715-25 PMID: 16231422
  18. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate.
    BMC Genomics. 2008 Dec 08;9:591 PMID: 19063729
  19. Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation.
    EMBO J. 2005 Feb 9;24(3):635-44 PMID: 15650748
  20. A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability.
    Nat Med. 2008 Dec;14(12):1384-9 PMID: 19029987
  21. Breast cancer classification and prognosis based on gene expression profiles from a population-based study.
    Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8 PMID: 12917485
  22. GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value.
    Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):365-73 PMID: 18268121
  23. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking.
    Science. 2005 May 20;308(5725):1171-4 PMID: 15905401
  24. Dissociation between steroid receptor expression and cell proliferation in the human breast.
    Cancer Res. 1997 Nov 15;57(22):4987-91 PMID: 9371488
  25. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
    J Clin Oncol. 2008 Mar 10;26(8):1331-7 PMID: 18268356
  26. Breast cancer incidence among atomic bomb survivors: implications for radiobiologic risk at low doses.
    J Natl Cancer Inst. 1979 Jan;62(1):17-21 PMID: 281571
  27. Regulation of mammary morphogenesis: evidence for extracellular matrix-mediated inhibition of ductal budding by transforming growth factor-beta 1.
    Dev Biol. 1992 Aug;152(2):354-62 PMID: 1644225
  28. Role of estrogen receptor-alpha in the anterior pituitary gland.
    Mol Endocrinol. 1997 Jun;11(6):674-81 PMID: 9171231
  29. Age at first birth and breast cancer risk.
    Bull World Health Organ. 1970;43(2):209-21 PMID: 5312521
  30. Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells.
    Breast Cancer Res. 2009;11(2):R20 PMID: 19386118
  31. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes.
    Clin Cancer Res. 2007 Apr 15;13(8):2329-34 PMID: 17438091
  32. Cancer susceptibility and the functions of BRCA1 and BRCA2.
    Cell. 2002 Jan 25;108(2):171-82 PMID: 11832208
  33. Detection of allelic imbalance indicates that a proportion of mammary hyperplasia of usual type are clonal, neoplastic proliferations.
    Lab Invest. 1996 Jan;74(1):129-35 PMID: 8569175
  34. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  35. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue.
    Breast Cancer Res Treat. 2001 May;67(2):93-109 PMID: 11519870
  36. Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties.
    Genes Dev. 2002 Mar 15;16(6):693-706 PMID: 11914275
  37. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal.
    Tissue Cell. 1997 Apr;29(2):239-53 PMID: 9149446
  38. Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium.
    Curr Biol. 2008 Jul 22;18(14):1094-9 PMID: 18635350
  39. Crypt stem cells as the cells-of-origin of intestinal cancer.
    Nature. 2009 Jan 29;457(7229):608-11 PMID: 19092804
  40. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
    N Engl J Med. 2009 Jul 9;361(2):123-34 PMID: 19553641
  41. Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells--implications for pregnancy-induced protection against breast cancer.
    Stem Cells. 2008 Dec;26(12):3205-9 PMID: 18787212
  42. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia.
    Development. 2007 Mar;134(6):1231-42 PMID: 17287253
  43. Molecular portraits of human breast tumours.
    Nature. 2000 Aug 17;406(6797):747-52 PMID: 10963602
  44. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer.
    Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12111-6 PMID: 17626182
  45. Purification and unique properties of mammary epithelial stem cells.
    Nature. 2006 Feb 23;439(7079):993-7 PMID: 16395311
  46. Integrin-dependent anchoring of a stem-cell niche.
    Nat Cell Biol. 2007 Dec;9(12):1413-8 PMID: 17982446
  47. The mammary microenvironment alters the differentiation repertoire of neural stem cells.
    Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14891-6 PMID: 18809919
  48. Molecular definition of breast tumor heterogeneity.
    Cancer Cell. 2007 Mar;11(3):259-73 PMID: 17349583
  49. Searching chromatin for stem cell identity.
    Cell. 2006 Apr 21;125(2):233-6 PMID: 16630812
  50. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression.
    Oncogene. 2005 Jan 20;24(4):552-60 PMID: 15580303
  51. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype.
    Clin Cancer Res. 2005 Jul 15;11(14):5175-80 PMID: 16033833
  52. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.
    J Cell Biol. 2009 Jun 1;185(5):811-26 PMID: 19487454
  53. Transcriptome analysis of the normal human mammary cell commitment and differentiation process.
    Cell Stem Cell. 2008 Jul 3;3(1):109-18 PMID: 18593563
  54. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells.
    Breast Cancer Res. 2006;8(1):R7 PMID: 16417656
  55. Pregnancy-associated breast cancer and metastasis.
    Nat Rev Cancer. 2006 Apr;6(4):281-91 PMID: 16557280
  56. Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers.
    Breast Cancer Res Treat. 2005 Mar;90(1):5-14 PMID: 15770521
  57. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.
    Nat Med. 2009 Aug;15(8):907-13 PMID: 19648928
  58. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
    Cell Stem Cell. 2007 Nov;1(5):555-67 PMID: 18371393
  59. A putative human breast stem cell population is enriched for steroid receptor-positive cells.
    Dev Biol. 2005 Jan 15;277(2):443-56 PMID: 15617686
  60. Steroid hormone receptor status of mouse mammary stem cells.
    J Natl Cancer Inst. 2006 Jul 19;98(14):1011-4 PMID: 16849684
  61. Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo.
    Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3871-6 PMID: 17360445
  62. Polycomb silencers control cell fate, development and cancer.
    Nat Rev Cancer. 2006 Nov;6(11):846-56 PMID: 17060944
  63. Do 'basal-like' breast cancers really exist?
    Nat Rev Cancer. 2009 Feb;9(2):128-34 PMID: 19132008
  64. A paracrine role for the epithelial progesterone receptor in mammary gland development.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5076-81 PMID: 9560231
  65. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.
    N Engl J Med. 2004 Aug 12;351(7):657-67 PMID: 15306667
  66. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?
    Cancer Cell. 2005 Jan;7(1):17-23 PMID: 15652746
  67. Notch signaling regulates mammary stem cell function and luminal cell-fate commitment.
    Cell Stem Cell. 2008 Oct 9;3(4):429-41 PMID: 18940734
  68. Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells.
    Nat Cell Biol. 2008 Jun;10(6):716-22 PMID: 18469806
  69. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.
    Cancer Cell. 2008 Feb;13(2):141-52 PMID: 18242514
  70. An entire functional mammary gland may comprise the progeny from a single cell.
    Development. 1998 May;125(10):1921-30 PMID: 9550724
  71. The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis.
    Cancer Res. 2008 Oct 1;68(19):7711-7 PMID: 18829523
  72. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases.
    Am J Pathol. 2003 Nov;163(5):2113-26 PMID: 14578209
  73. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland.
    J Cell Sci. 1988 May;90 ( Pt 1):173-83 PMID: 3198708
  74. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.
    Cancer Res. 2006 Jun 15;66(12):6063-71 PMID: 16778178
  75. Delineating the epithelial hierarchy in the mouse mammary gland.
    Cold Spring Harb Symp Quant Biol. 2008;73:469-78 PMID: 19022771
  76. BRCA1 regulates human mammary stem/progenitor cell fate.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1680-5 PMID: 18230721
  77. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.
    Breast Cancer Res. 2004;6(6):R605-15 PMID: 15535842
  78. Mapping mammary gland architecture using multi-scale in situ analysis.
    Integr Biol (Camb). 2009 Jan;1(1):80-9 PMID: 20023794
  79. The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy.
    Dev Biol. 2006 May 15;293(2):565-80 PMID: 16581056
  80. A functional Notch-survivin gene signature in basal breast cancer.
    Breast Cancer Res. 2008;10(6):R97 PMID: 19025652
  81. Nuclear signalling by tumour-associated antigen EpCAM.
    Nat Cell Biol. 2009 Feb;11(2):162-71 PMID: 19136966
  82. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells.
    Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8 PMID: 14668450
  83. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands.
    Development. 2005 Feb;132(4):681-7 PMID: 15647322
  84. Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer.
    Cell Stem Cell. 2008 Jan 10;2(1):90-102 PMID: 18371425
  85. The Ets transcription factor Elf5 specifies mammary alveolar cell fate.
    Genes Dev. 2008 Mar 1;22(5):581-6 PMID: 18316476
  86. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
    Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 PMID: 11553815
  87. Notch signaling: cell fate control and signal integration in development.
    Science. 1999 Apr 30;284(5415):770-6 PMID: 10221902
  88. Pregnancy and stem cell behavior.
    J Mammary Gland Biol Neoplasia. 2005 Jan;10(1):25-36 PMID: 15886884
  89. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.
    Cancer Res. 2009 May 15;69(10):4116-24 PMID: 19435916
  90. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice.
    Cancer Res. 1959 Jun;19(5):515-20 PMID: 13663040
  91. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.
    Nat Genet. 2008 May;40(5):499-507 PMID: 18443585
  92. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells.
    Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4158-63 PMID: 15020770
  93. Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A.
    Genes Dev. 2009 Oct 15;23(20):2382-7 PMID: 19833766
  94. Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer.
    Breast Cancer Res. 2005;7(4):143-8 PMID: 15987465
  95. Hallmarks of 'BRCAness' in sporadic cancers.
    Nat Rev Cancer. 2004 Oct;4(10):814-9 PMID: 15510162
  96. Wnt signalling in stem cells and cancer.
    Nature. 2005 Apr 14;434(7035):843-50 PMID: 15829953
  97. Reconstruction of functionally normal and malignant human breast tissues in mice.
    Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4966-71 PMID: 15051869
  98. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1.
    Genes Dev. 1993 Dec;7(12A):2308-17 PMID: 8253379
  99. TA-p63-gamma regulates expression of DeltaN-p63 in a manner that is sensitive to p53.
    Oncogene. 2006 Apr 13;25(16):2349-59 PMID: 16331262
  100. Generation of a functional mammary gland from a single stem cell.
    Nature. 2006 Jan 5;439(7072):84-8 PMID: 16397499
  101. Influence of cell division on an aging process. Life span of mouse mammary epithelium during serial propagation in vivo.
    Exp Cell Res. 1971 Mar;65(1):27-32 PMID: 5549550
  102. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.
    Clin Cancer Res. 2008 Mar 1;14(5):1368-76 PMID: 18316557
  103. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development.
    Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5455-60 PMID: 17369357
  104. A novel method for growing human breast epithelium in vivo using mouse and human mammary fibroblasts.
    Endocrinology. 2002 Dec;143(12):4886-96 PMID: 12446616
  105. Changes in the parous rat mammary gland environment are involved in parity-associated protection against mammary carcinogenesis.
    Anticancer Res. 1998 Nov-Dec;18(6A):4115-21 PMID: 9891455
  106. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells.
    Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):618-23 PMID: 17202265
  107. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland.
    J Cell Biol. 2007 Jan 1;176(1):19-26 PMID: 17190790
  108. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells.
    Genes Dev. 2003 May 15;17(10):1253-70 PMID: 12756227
  109. BRCA1 and BRCA2: 1994 and beyond.
    Nat Rev Cancer. 2004 Sep;4(9):665-76 PMID: 15343273
  110. Resident macrophages influence stem cell activity in the mammary gland.
    Breast Cancer Res. 2009;11(4):R62 PMID: 19706193
  111. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.
    Nat Cell Biol. 2007 Feb;9(2):201-9 PMID: 17187062
  112. Postnatal mammary gland morphogenesis.
    Microsc Res Tech. 2001 Jan 15;52(2):155-62 PMID: 11169863
  113. Diverse mechanisms regulate stem cell self-renewal.
    Curr Opin Cell Biol. 2004 Dec;16(6):700-7 PMID: 15530784
  114. Breast differentiation and its implication in cancer prevention.
    Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):931s-6s PMID: 15701889
  115. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors.
    Genome Biol. 2007;8(5):R76 PMID: 17493263
  116. Transplantability and life span of mammary gland during serial transplantation in mice.
    Nature. 1967 Jan 14;213(5072):193-4 PMID: 6030584
  117. Notch signaling in stem cell systems.
    Stem Cells. 2006 Nov;24(11):2437-47 PMID: 16888285
  118. The mammary fat pad.
    J Mammary Gland Biol Neoplasia. 1998 Apr;3(2):109-16 PMID: 10819521
  119. Cell size and shape changes in the myoepithelium of the mammary gland during differentiation.
    Anat Rec. 1986 Nov;216(3):405-15 PMID: 3789423
  120. Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype.
    Breast Cancer Res Treat. 1996;39(1):21-31 PMID: 8738603
  121. Estrogen receptor-alpha and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands.
    Breast Cancer Res. 2006;8(4):R49 PMID: 16882347
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1849509
Email
[email protected]
Published
2009-11-15
Pages
2563-77
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2779757
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1849509 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2