Development, Vol 125, Issue 10 1921-1930, Copyright © 1998 by Company of Biologists

JOURNAL ARTICLES

An entire functional mammary gland may comprise the progeny from a single cell

EC Kordon and GH Smith
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892, USA.

Any epithelial portion of a normal mouse mammary gland can reproduce an entire functional gland when transplanted into an epithelium-free mammary fat pad. Mouse mammary hyperplasias and tumors are clonal dominant populations and probably represent the progeny of a single transformed cell. Our study provides evidence that single multipotent stem cells positioned throughout the mature fully developed mammary gland have the capacity to produce sufficient differentiated progeny to recapitulate an entire functional gland. Our evidence also demonstrates that these stem cells are self-renewing and are found with undiminished capacities in the newly regenerated gland. We have taken advantage of an experimental model where mouse mammary tumor virus infects mammary epithelial cells and inserts a deoxyribonucleic acid copy(ies) of its genome during replication. The insertions occur randomly within the somatic genome. CzechII mice have no endogenous nucleic acid sequence homology with mouse mammary tumor virus; therefore all viral insertions may be detected by Southern analysis provided a sufficient number of cells contain a specific insertional event. Transplantation of random fragments of infected CzechII mammary gland produced clonal-dominant epithelial populations in epithelium-free mammary fat pads. Serial transplantation of pieces of the clonally derived outgrowths produced second generation glands possessing the same viral insertion sites providing evidence for self-renewal of the original stem cell. Limiting dilution studies with cell cultures derived from third generation clonal outgrowths demonstrated that three multipotent but distinct mammary epithelial progenitors were present in clonally derived mammary epithelial populations. Estimation of the potential number of multipotent epithelial cells that may be evolved from an individual mammary-specific stem cell by self-renewal is in the order of 10(12)-10(13). Therefore, one stem cell might easily account for the renewal of mammary epithelium over several transplant generations.

This article has been cited by other articles:

				M.-L. Asselin-Labat, F. Vaillant, M. Shackleton, T. Bouras, G.J. Lindeman, and J.E. Visvader Delineating the Epithelial Hierarchy in the Mouse Mammary Gland Cold Spring Harb Symp Quant Biol, November 19, 2008; (2008) sqb.2008.73.020v2. [Abstract] [PDF]

				R.U. Lukacs, D.A. Lawson, L. Xin, Y. Zong, I. Garraway, A.S. Goldstein, S. Memarzadeh, and O.N. Witte Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression Cold Spring Harb Symp Quant Biol, November 6, 2008; (2008) sqb.2008.73.012v1. [Abstract] [PDF]

				M. J. Bissell and J. Inman Reprogramming stem cells is a microenvironmental task PNAS, October 14, 2008; 105(41): 15637 - 15638. [Full Text] [PDF]

				B. W. Booth, D. L. Mack, A. Androutsellis-Theotokis, R. D. G. McKay, C. A. Boulanger, and G. H. Smith The mammary microenvironment alters the differentiation repertoire of neural stem cells PNAS, September 30, 2008; 105(39): 14891 - 14896. [Abstract] [Full Text] [PDF]

				M. Kakarala and M. S. Wicha Implications of the Cancer Stem-Cell Hypothesis for Breast Cancer Prevention and Therapy J. Clin. Oncol., June 10, 2008; 26(17): 2813 - 2820. [Abstract] [Full Text] [PDF]

				X.-Y. Wang, Y. Yin, H. Yuan, T. Sakamaki, H. Okano, and R. I. Glazer Musashi1 Modulates Mammary Progenitor Cell Expansion through Proliferin-Mediated Activation of the Wnt and Notch Pathways Mol. Cell. Biol., June 1, 2008; 28(11): 3589 - 3599. [Abstract] [Full Text] [PDF]

				E. L. Annen, C. M. Stiening, B. A. Crooker, A. C. Fitzgerald, and R. J. Collier Effect of continuous milking and prostaglandin E2 on milk production and mammary epithelial cell turnover, ultrastructure, and gene expression J Anim Sci, May 1, 2008; 86(5): 1132 - 1144. [Abstract] [Full Text] [PDF]

				S. R. Oakes, M. J. Naylor, M.-L. Asselin-Labat, K. D. Blazek, M. Gardiner-Garden, H. N. Hilton, M. Kazlauskas, M. A. Pritchard, L. A. Chodosh, P. L. Pfeffer, et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate Genes & Dev., March 1, 2008; 22(5): 581 - 586. [Abstract] [Full Text] [PDF]

				A. V. Capuco Identification of Putative Bovine Mammary Epithelial Stem Cells by Their Retention of Labeled DNA Strands Experimental Biology and Medicine, November 1, 2007; 232(10): 1381 - 1390. [Abstract] [Full Text] [PDF]

				M.-J. Liao, C. C. Zhang, B. Zhou, D. B. Zimonjic, S. A. Mani, M. Kaba, A. Gifford, F. Reinhardt, N. C. Popescu, W. Guo, et al. Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have In vivo Repopulating Activity Cancer Res., September 1, 2007; 67(17): 8131 - 8138. [Abstract] [Full Text] [PDF]

				C. A. Boulanger, D. L. Mack, B. W. Booth, and G. H. Smith Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo PNAS, March 6, 2007; 104(10): 3871 - 3876. [Abstract] [Full Text] [PDF]

				S. A. Gestl, T. L. Leonard, J. L. Biddle, M. T. Debies, and E. J. Gunther Dormant Wnt-Initiated Mammary Cancer Can Participate in Reconstituting Functional Mammary Glands Mol. Cell. Biol., January 1, 2007; 27(1): 195 - 207. [Abstract] [Full Text] [PDF]

				E. L. Annen, A. C. Fitzgerald, P. C. Gentry, M. A. McGuire, A. V. Capuco, L. H. Baumgard, and R. J. Collier Effect of Continuous Milking and Bovine Somatotropin Supplementation on Mammary Epithelial Cell Turnover J Dairy Sci, January 1, 2007; 90(1): 165 - 183. [Abstract] [Full Text] [PDF]

				C.E. Gargett Uterine stem cells: What is the evidence? Hum. Reprod. Update, January 1, 2007; 13(1): 87 - 101. [Abstract] [Full Text] [PDF]

				P. Tang, X. Wang, L. Schiffhauer, J. Wang, P. Bourne, Q. Yang, A. Quinn, and S. I. Hajdu Relationship between Nuclear Grade of Ductal Carcinoma in situ and Cell Origin Markers. Ann. Clin. Lab. Sci., December 1, 2006; 36(1): 16 - 22. [Abstract] [Full Text] [PDF]

				C. Lindvall, N. C. Evans, C. R. Zylstra, Y. Li, C. M. Alexander, and B. O. Williams The Wnt Signaling Receptor Lrp5 Is Required for Mammary Ductal Stem Cell Activity and Wnt1-induced Tumorigenesis J. Biol. Chem., November 17, 2006; 281(46): 35081 - 35087. [Abstract] [Full Text] [PDF]

				A. Gattelli, M. N. Zimberlin, R. P. Meiss, L. H. Castilla, and E. C. Kordon Selection of Early-Occurring Mutations Dictates Hormone-Independent Progression in Mouse Mammary Tumor Lines J. Virol., November 15, 2006; 80(22): 11409 - 11415. [Abstract] [Full Text] [PDF]

				J. E. Visvader and G. J. Lindeman Mammary stem cells and mammopoiesis. Cancer Res., October 15, 2006; 66(20): 9798 - 9801. [Abstract] [Full Text] [PDF]

				I. Mikaelian, M. Hovick, K. A. Silva, L. M. Burzenski, L. D. Shultz, C. L. Ackert-Bicknell, G. A. Cox, and J. P. Sundberg Expression of Terminal Differentiation Proteins Defines Stages of Mouse Mammary Gland Development Vet. Pathol., January 1, 2006; 43(1): 36 - 49. [Abstract] [Full Text] [PDF]

				M. S. Holland and R. E. Holland The Cellular Perspective on Mammary Gland Development: Stem/Progenitor Cells and Beyond J Dairy Sci, May 1, 2005; 88(e_suppl_1): E1 - E8. [Abstract] [Full Text] [PDF]

				F. Behbod and J. M. Rosen Will cancer stem cells provide new therapeutic targets? Carcinogenesis, April 1, 2005; 26(4): 703 - 711. [Abstract] [Full Text] [PDF]

				A. L. Welm, S. Kim, B. E. Welm, and J. M. Bishop MET and MYC cooperate in mammary tumorigenesis PNAS, March 22, 2005; 102(12): 4324 - 4329. [Abstract] [Full Text] [PDF]

				G. H. Smith Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands Development, February 15, 2005; 132(4): 681 - 687. [Abstract] [Full Text] [PDF]

				M. Del Vecchio and V. Eusebi Tumors of the Breast Showing Dual Differentiation: A Review International Journal of Surgical Pathology, October 1, 2004; 12(4): 345 - 350. [PDF]

				B. Y. Liu, S. P. McDermott, S. S. Khwaja, and C. M. Alexander The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells PNAS, March 23, 2004; 101(12): 4158 - 4163. [Abstract] [Full Text] [PDF]

				W D Foulkes BRCA1 functions as a breast stem cell regulator J. Med. Genet., January 1, 2004; 41(1): 1 - 5. [Abstract] [Full Text] [PDF]

				M. Niku, L. Ilmonen, T. Pessa-Morikawa, and A. Iivanainen Limited Contribution of Circulating Cells to the Development and Maintenance of Nonhematopoietic Bovine Tissues Stem Cells, January 1, 2004; 22(1): 12 - 20. [Abstract] [Full Text] [PDF]

				S. Desrivieres, T. Prinz, N. Castro-Palomino Laria, M. Meyer, G. Boehm, U. Bauer, J. Schafer, T. Neumann, C. Shemanko, and B. Groner Comparative Proteomic Analysis of Proliferating and Functionally Differentiated Mammary Epithelial Cells Mol. Cell. Proteomics, October 1, 2003; 2(10): 1039 - 1054. [Abstract] [Full Text] [PDF]

				T. G. Davenport, L. A. Jerome-Majewska, and V. E. Papaioannou Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome Development, May 15, 2003; 130(10): 2263 - 2273. [Abstract] [Full Text] [PDF]

				G. Dontu, W. M. Abdallah, J. M. Foley, K. W. Jackson, M. F. Clarke, M. J. Kawamura, and M. S. Wicha In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells Genes & Dev., May 15, 2003; 17(10): 1253 - 1270. [Abstract] [Full Text] [PDF]

				J. E. Dick Breast cancer stem cells revealed PNAS, April 1, 2003; 100(7): 3547 - 3549. [Full Text] [PDF]

				S. B. Tepera, P. D. McCrea, and J. M. Rosen A {beta}-catenin survival signal is required for normal lobular development in the mammary gland J. Cell Sci., March 15, 2003; 116(6): 1137 - 1149. [Abstract] [Full Text] [PDF]

				K.-U. Wagner, C. A. Boulanger, M. D. Henry, M. Sgagias, L. Hennighausen, and G. H. Smith An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal Development, March 5, 2003; 129(6): 1377 - 1386. [Abstract] [Full Text] [PDF]

				A. V. Capuco, S. E. Ellis, S. A. Hale, E. Long, R. A. Erdman, X. Zhao, and M. J. Paape Lactation persistency: Insights from mammary cell proliferation studies J Anim Sci, March 1, 2003; 81(suppl_3): 18 - 31. [Abstract] [Full Text] [PDF]

				M.-A. Deugnier, M. M. Faraldo, B. Janji, P. Rousselle, J. P. Thiery, and M. A. Glukhova EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties J. Cell Biol., November 7, 2002; 159(3): 453 - 463. [Abstract] [Full Text] [PDF]

				J. DiRenzo, S. Signoretti, N. Nakamura, R. Rivera-Gonzalez, W. Sellers, M. Loda, and M. Brown Growth Factor Requirements and Basal Phenotype of an Immortalized Mammary Epithelial Cell Line Cancer Res., January 1, 2002; 62(1): 89 - 98. [Abstract] [Full Text] [PDF]

				K. Miyoshi, J. M. Shillingford, G. H. Smith, S. L. Grimm, K.-U. Wagner, T. Oka, J. M. Rosen, G. W. Robinson, and L. Hennighausen Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium J. Cell Biol., November 12, 2001; 155(4): 531 - 542. [Abstract] [Full Text] [PDF]

				P. L. Welcsh and M.-C. King BRCA1 and BRCA2 and the genetics of breast and ovarian cancer Hum. Mol. Genet., April 1, 2001; 10(7): 705 - 713. [Abstract] [Full Text] [PDF]

				G. W. Robinson, L. Hennighausen, and P. F. Johnson Side-branching in the mammary gland: the progesterone-Wnt connection Genes & Dev., April 15, 2000; 14(8): 889 - 894. [Full Text]

				G. Shyamala, X. Yang, R. D. Cardiff, and E. Dale Impact of progesterone receptor on cell-fate decisions during mammary gland development PNAS, March 28, 2000; 97(7): 3044 - 3049. [Abstract] [Full Text] [PDF]

				S Naylor, M. Smalley, D Robertson, B. Gusterson, P. Edwards, and T. Dale Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium J. Cell Sci., January 6, 2000; 113(12): 2129 - 2138. [Abstract] [PDF]

				J. MacDougall and L. Matrisian Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes J. Cell Sci., January 2, 2000; 113(3): 409 - 423. [Abstract] [PDF]

				M. J. Smalley, J. Titley, H. Paterson, N. Perusinghe, C. Clarke, and M. J. O'Hare Differentiation of Separated Mouse Mammary Luminal Epithelial and Myoepithelial Cells Cultured on EHS Matrix Analyzed by Indirect Immunofluorescence of Cytoskeletal Antigens J. Histochem. Cytochem., December 1, 1999; 47(12): 1513 - 1524. [Abstract] [Full Text]