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.
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
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.
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.
Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998;125:1921–30.
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.
Smith GH, Boulanger CA. Mammary epithelial stem cells: Transplantation and self-renewal analysis. Cell Prolif 36 (Suppl) 2003;1:3–15.
Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004;51:1–28.
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.
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.
Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis. 2005;26:708–11. doi:10.1093/carcin/bgh293
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.
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.
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.
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.
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.
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.
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.
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.
Clarke RB, Anderson E, Howell A, Potten CS. Regulation of human breast epithelial stem cells. Cell Prolif 36 (Suppl 1) 2003;45–58.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48–58.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11.
Dai C, Holland EC. Astrocyte differentiation states and glioma formation. Cancer J 2003;9:72–81.
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.
Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia 2004;9:119–31.
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.
Alonso L, Fuchs E. Stem cells in the skin: Waste not, Wnt not. Genes Dev 2003;17:1189–1200.
Rattis FM, Voermans C, Reya T. Wnt signaling in the stem cell niche. Curr Opin Hematol 2004;11:88–94.
Sancho E, Batlle E, Clevers H. Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 2004;20:695–723.
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.
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.
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.
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.
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.
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.
Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 2004;4:814–19.
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.
Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411:1017–21.
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.
Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 2004.
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.
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.
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.
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.
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.
Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 2005;132:681–7.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Issue Date:
DOI: https://doi.org/10.1007/s10911-005-2537-2