Skip to main content

Advertisement

Log in

Stem/Progenitor Cells in Mouse Mammary Gland Development and Breast Cancer

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Breast cancer is a genetically and clinically heterogeneous disease. It is unclear whether different target cells contribute to this heterogeneity and which cell types are most susceptible to oncogenesis. Stem cells are speculated to be the cellular origin of at least a subset of human breast cancers. To begin to address these issues, we have isolated and characterized cell populations enriched in normal mammary stem/progenitors and have studied the expression of putative stem/progenitor markers in tumors derived from genetically engineered mice. Specifically, transgenic activation of Wnt signaling in the mammary gland induces tumors comprised of epithelial and myoepithelial cells harboring the same genetic defect implying that the tumor arose from transformation of a bipotent progenitor cell. On the other hand, transgenic activation of Neu signaling induces tumors comprising cells of more limited lineage capacity. Thus, the heterogeneity of different breast cancers may reflect the activation of different oncogenic pathways, different cellular targets in which these genetic changes occur, or both.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

SP:

side-population

Sca-1:

stem cell antigen-1

MMTV:

mouse mammary tumor virus

LRC:

label-retaining cell

BCRP1:

breast cancer resistance protein-1

MEC:

mammary epithelial cell

TEB:

terminal end bud

PyMT:

polyoma middle T antigen

WAP:

whey acidic protein

References

  1. DeOme KB, Faulkin LJ, Jr, Bern HA, Blair PB. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 1959;19:515–20.

    CAS  PubMed  Google Scholar 

  2. Smith GH, Medina D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J Cell Sci 90 (Pt 1) 1988;173–83.

    PubMed  Google Scholar 

  3. Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998;125:1921–30.

    CAS  PubMed  Google Scholar 

  4. Smith GH. 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;39:21–31.

    CAS  PubMed  Google Scholar 

  5. Smith GH, Boulanger CA. Mammary epithelial stem cells: Transplantation and self-renewal analysis. Cell Prolif 36 (Suppl) 2003;1:3–15.

    Article  CAS  PubMed  Google Scholar 

  6. Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004;51:1–28.

    PubMed  Google Scholar 

  7. Land CE, McGregor DH. Breast cancer incidence among atomic bomb survivors: Implications for radiobiologic risk at low doses. J Natl Cancer Inst 1979;62:17–21.

    CAS  PubMed  Google Scholar 

  8. Rosen PR, Groshen S, Saigo PE, Kinne DW, Hellman S. A long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin Oncol 1989;7:355–66.

    CAS  PubMed  Google Scholar 

  9. Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis. 2005;26:708–11. doi:10.1093/carcin/bgh293

    Article  Google Scholar 

  10. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature 2004;432:396–401.

    Article  CAS  PubMed  Google Scholar 

  11. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983–88.

    Article  CAS  PubMed  Google Scholar 

  12. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657–67.

    Article  CAS  PubMed  Google Scholar 

  13. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 2002;245:42–56.

    Article  CAS  PubMed  Google Scholar 

  14. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183:1797–1806.

    Article  CAS  PubMed  Google Scholar 

  15. Alvi AJ, Clayton H, Joshi C, Enver T, Ashworth A, Vivanco MM, Dale TC, Smalley MJ. Functional and molecular characterisation of mammary side population cells. Breast Cancer Res 2003;5:R1–8.

    Article  PubMed  Google Scholar 

  16. Clayton H, Titley I, Vivanco M. Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res 2004;297:444–60.

    Article  CAS  PubMed  Google Scholar 

  17. Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast population is enriched for steroid-receptor-positive cells Dev Biol 2005;277:443–56.

    Article  CAS  PubMed  Google Scholar 

  18. Clarke RB, Anderson E, Howell A, Potten CS. Regulation of human breast epithelial stem cells. Cell Prolif 36 (Suppl 1) 2003;45–58.

    Article  CAS  Google Scholar 

  19. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48–58.

    CAS  PubMed  Google Scholar 

  20. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004;101:14228–33.

    Article  CAS  PubMed  Google Scholar 

  21. Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, Sorrentino BP, Schuetz JD. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 2004;279:24218–25.

    Article  CAS  PubMed  Google Scholar 

  22. Triel C, Vestergaard ME, Bolund L, Jensen TG, Jensen UB. Side population cells in human and mouse epidermis lack stem cell characteristics. Exp Cell Res 2004;295:79–90.

    Article  CAS  PubMed  Google Scholar 

  23. Terunuma A, Jackson KL, Kapoor V, Telford WG, Vogel JC. Side population keratinocytes resembling bone marrow side population stem cells are distinct from label-retaining keratinocyte stem cells. J Invest Dermatol 2003;121:1095–03.

    Article  CAS  PubMed  Google Scholar 

  24. Rock KL, Reiser H, Bamezai A, McGrew J, Benacerraf B. The LY-6 locus: A multigene family encoding phosphatidylinositol-anchored membrane proteins concerned with T-cell activation. Immunol Rev 1989;111:195–224.

    CAS  PubMed  Google Scholar 

  25. Danielson KG, Oborn CJ, Durban EM, Butel JS, Medina D. Epithelial mouse mammary cell line exhibiting normal morphogenesis in vivo and functional differentiation in vitro. Proc Natl Acad Sci USA 1984;81:3756–60.

    CAS  PubMed  Google Scholar 

  26. Smith GH, Mehrel T, Roop DR. Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. Cell Growth Differ 1990;1:161–70.

    CAS  PubMed  Google Scholar 

  27. Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE. 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;100:15853–58.

    Article  CAS  PubMed  Google Scholar 

  28. Paladini RD, Takahashi K, Bravo NS, Coulombe PA. Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: Defining a potential role for keratin 16. J Cell Biol 1996;132:381–97.

    Article  CAS  PubMed  Google Scholar 

  29. Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 1994;70:6–22.

    CAS  PubMed  Google Scholar 

  30. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  31. Dai C, Holland EC. Astrocyte differentiation states and glioma formation. Cancer J 2003;9:72–81.

    CAS  PubMed  Google Scholar 

  32. Hatsell S, Rowlands T, Hiremath M, Cowin P. Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 2003;8:145–58.

    Article  PubMed  Google Scholar 

  33. Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia 2004;9:119–31.

    Article  PubMed  Google Scholar 

  34. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004;10:55–63.

    Article  CAS  PubMed  Google Scholar 

  35. Alonso L, Fuchs E. Stem cells in the skin: Waste not, Wnt not. Genes Dev 2003;17:1189–1200.

    Article  CAS  PubMed  Google Scholar 

  36. Rattis FM, Voermans C, Reya T. Wnt signaling in the stem cell niche. Curr Opin Hematol 2004;11:88–94.

    Article  CAS  PubMed  Google Scholar 

  37. Sancho E, Batlle E, Clevers H. Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 2004;20:695–723.

    CAS  PubMed  Google Scholar 

  38. Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci USA 2004;101:4158–63.

    Article  CAS  PubMed  Google Scholar 

  39. Cui XS, Donehower LA. Differential gene expression in mouse mammary adenocarcinomas in the presence and absence of wild type p53. Oncogene 2000;19:5988–96.

    CAS  PubMed  Google Scholar 

  40. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, Nicholson RI, Ellis IO. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 2004;203:661–71.

    PubMed  Google Scholar 

  41. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000;406:747–52.

    CAS  PubMed  Google Scholar 

  42. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron J. S, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003;100:8418–23.

    CAS  PubMed  Google Scholar 

  43. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869–74.

    CAS  PubMed  Google Scholar 

  44. Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 2004;4:814–19.

    CAS  PubMed  Google Scholar 

  45. Andrechek ER, Hardy WR, Laing MA, Muller WJ. Germ-line expression of an oncogenic erbB2 allele confers resistance to erbB2-induced mammary tumorigenesis. Proc Natl Acad Sci USA 2004;101:4984–89.

    CAS  PubMed  Google Scholar 

  46. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411:1017–21.

    Article  CAS  PubMed  Google Scholar 

  47. Henry MD, Triplett AA, Oh KB, Smith GH, Wagner KU. Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-Neu transgenic mice. Oncogene 2004;23:6980–85.

    CAS  PubMed  Google Scholar 

  48. Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 2004.

  49. Morrison BW, Leder P. neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene 1994;9:3417–26.

    CAS  PubMed  Google Scholar 

  50. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003;17:1253–70.

    Article  CAS  PubMed  Google Scholar 

  51. D’Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD, Chodosh LA. c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med 2001;7:235–39.

    CAS  PubMed  Google Scholar 

  52. Fisher GH, Orsulic S, Holland E, Hively WP, Li Y, Lewis BC, Williams BO, Varmus HE. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 1999;18:5253–60.

    CAS  PubMed  Google Scholar 

  53. Lewis BC, Chinnasamy N, Morgan RA, Varmus HE. Development of an avian leukosis-sarcoma virus subgroup A pseudotyped lentiviral vector. J Virol 2001;75:9339–44.

    CAS  PubMed  Google Scholar 

  54. Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 2005;132:681–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeffrey M. Rosen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Y., Rosen, J.M. Stem/Progenitor Cells in Mouse Mammary Gland Development and Breast Cancer. J Mammary Gland Biol Neoplasia 10, 17–24 (2005). https://doi.org/10.1007/s10911-005-2537-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-005-2537-2

Navigation