Advertisement

Cellular and Molecular Life Sciences

, Volume 72, Issue 8, pp 1577–1583 | Cite as

Mammary lineage tracing: the coming of age

  • Sanja Sale
  • Kresimir Pavelic
Review

Abstract

Identification and characterization of the normal epithelial lineages in the mammary gland is a fundamental step in understanding both development and cellular origin of cancer. In contrast to other tissues where lineage tracing has been widely accepted as a method of choice for dissecting the stem cell hierarchy, mammary gland has long remained a challenge due to its unique developmental and topological features. Recent advances in high-resolution single-cell imaging, combined with the use of inducible Cre-recombinase and in situ cell ablation, have provided unprecedented insight into mammary epithelial cell composition and function. Here, we briefly summarize and compare different mammary gland lineage tracing strategies, examine associated caveats and discuss future challenges and opportunities.

Keywords

Breast Lineages Fate mapping In situ cell ablation Cell-of-origin Genetically engineered mouse models Topological context 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Deome KB, Faulkin LJ Jr, Bern HA, Blair PB (1959) Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 19(5):515–520PubMedGoogle Scholar
  2. 2.
    Smith GH (1996) Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat 39(1):21–31CrossRefPubMedGoogle Scholar
  3. 3.
    Kordon EC, Smith GH (1998) An entire functional mammary gland may comprise the progeny from a single cell. Development 125(10):1921–1930PubMedGoogle Scholar
  4. 4.
    Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE (2006) Generation of a functional mammary gland from a single stem cell. Nature 439(7072):84–88CrossRefPubMedGoogle Scholar
  5. 5.
    Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439(7079):993–997PubMedGoogle Scholar
  6. 6.
    Sleeman KE, Kendrick H, Robertson D, Isacke CM, Ashworth A, Smalley MJ (2007) Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol 176(1):19–26CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Shehata M, Teschendorff A, Sharp G, Novcic N, Russell IA, Avril S, Prater M, Eirew P, Caldas C, Watson CJ et al (2012) Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland. Breast Cancer Res BCR 14(5):R134CrossRefGoogle Scholar
  8. 8.
    Sleeman KE, Kendrick H, Ashworth A, Isacke CM, Smalley MJ (2006) CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast cancer Res BCR 8(1):R7CrossRefGoogle Scholar
  9. 9.
    Spike BT, Engle DD, Lin JC, Cheung SK, La J, Wahl GM (2012) A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell 10(2):183–197CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Smalley MJ, Kendrick H, Sheridan JM, Regan JL, Prater MD, Lindeman GJ, Watson CJ, Visvader JE, Stingl J (2012) Isolation of mouse mammary epithelial subpopulations: a comparison of leading methods. J Mammary Gland Biol Neoplasia 17(2):91–97CrossRefPubMedGoogle Scholar
  11. 11.
    Bai L, Rohrschneider LR (2010) s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue. Genes Dev 24(17):1882–1892CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Plaks V, Brenot A, Lawson DA, Linnemann JR, Van Kappel EC, Wong KC, de Sauvage F, Klein OD, Werb Z (2013) Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep 3(1):70–78CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Makarem M, Kannan N, Nguyen LV, Knapp DJ, Balani S, Prater MD, Stingl J, Raouf A, Nemirovsky O, Eirew P et al (2013) Developmental changes in the in vitro activated regenerative activity of primitive mammary epithelial cells. PLoS Biol 11(8):e1001630CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Regan JL, Kendrick H, Magnay FA, Vafaizadeh V, Groner B, Smalley MJ (2012) c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31(7):869–883CrossRefPubMedGoogle Scholar
  15. 15.
    Zeng YA, Nusse R (2010) Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6(6):568–577CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Machado HL, Kittrell FS, Edwards D, White AN, Atkinson RL, Rosen JM, Medina D, Lewis MT (2013) Separation by cell size enriches for mammary stem cell repopulation activity. Stem Cells Transl Med 2(3):199–203CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Kaanta AS, Virtanen C, Selfors LM, Brugge JS, Neel BG (2013) Evidence for a multipotent mammary progenitor with pregnancy-specific activity. Breast Cancer Res BCR 15(4):R65CrossRefGoogle Scholar
  18. 18.
    Nguyen LV, Makarem M, Carles A, Moksa M, Kannan N, Pandoh P, Eirew P, Osako T, Kardel M, Cheung AM et al (2014) Clonal analysis via barcoding reveals diverse growth and differentiation of transplanted mouse and human mammary stem cells. Cell Stem Cell 14(2):253–263CrossRefPubMedGoogle Scholar
  19. 19.
    Oakes SR, Gallego-Ortega D, Ormandy CJ (2014) The mammary cellular hierarchy and breast cancer. Cell Mol Life Sci CMLS 71:4301–4324CrossRefGoogle Scholar
  20. 20.
    Visvader JE, Stingl J (2014) Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev 28(11):1143–1158CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Prater MD, Petit V, Alasdair Russell I, Giraddi RR, Shehata M, Menon S, Schulte R, Kalajzic I, Rath N, Olson MF et al (2014) Mammary stem cells have myoepithelial cell properties. Nat Cell Biol 16(10):942–950, 941–947Google Scholar
  22. 22.
    Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, Sharma N, Dekoninck S, Blanpain C (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479(7372):189–193CrossRefPubMedGoogle Scholar
  23. 23.
    van Amerongen R, Bowman AN, Nusse R (2012) Developmental stage and time dictate the fate of Wnt/beta-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11(3):387–400CrossRefPubMedGoogle Scholar
  24. 24.
    de Visser KE, Ciampricotti M, Michalak EM, Tan DW, Speksnijder EN, Hau CS, Clevers H, Barker N, Jonkers J (2012) Developmental stage-specific contribution of LGR5(+) cells to basal and luminal epithelial lineages in the postnatal mammary gland. J Pathol 228(3):300–309CrossRefPubMedGoogle Scholar
  25. 25.
    Chang TH, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM (2014) New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res BCR 16(1):R1CrossRefGoogle Scholar
  26. 26.
    Kretzschmar K, Watt FM (2012) Lineage tracing. Cell 148(1–2):33–45CrossRefPubMedGoogle Scholar
  27. 27.
    Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH (2002) An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development 129(6):1377–1386PubMedGoogle Scholar
  28. 28.
    Sale S, Lafkas D, Artavanis-Tsakonas S (2013) Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15(5):451–460CrossRefPubMedGoogle Scholar
  29. 29.
    Tao L, van Bragt MP, Laudadio E, Li Z (2014) Lineage tracing of mammary epithelial cells using cell-type-specific cre-expressing adenoviruses. Stem Cell Reports 2(6):770–779CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Lafkas D, Rodilla V, Huyghe M, Mourao L, Kiaris H, Fre S (2013) Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J Cell Biol 203(1):47–56CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Wang D, Cai C, Dong X, Yu QC, Zhang XO, Yang L, Zeng YA (2014) Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517:81–84CrossRefPubMedGoogle Scholar
  32. 32.
    Shehata M, van Amerongen R, Zeeman AL, Giraddi RR, Stingl J (2014) The influence of tamoxifen on normal mouse mammary gland homeostasis. Breast Cancer Res BCR 16(4):411CrossRefGoogle Scholar
  33. 33.
    Rios AC, Fu NY, Lindeman GJ, Visvader JE (2014) In situ identification of bipotent stem cells in the mammary gland. Nature 506(7488):322–327CrossRefPubMedGoogle Scholar
  34. 34.
    Saito M, Iwawaki T, Taya C, Yonekawa H, Noda M, Inui Y, Mekada E, Kimata Y, Tsuru A, Kohno K (2001) Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nat Biotechnol 19(8):746–750CrossRefPubMedGoogle Scholar
  35. 35.
    Waddington CH (1957) The strategy of the genes; a discussion of some aspects of theoretical biology. Allen & Unwin, LondonGoogle Scholar
  36. 36.
    Chepko G, Smith GH (1997) Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 29(2):239–253CrossRefPubMedGoogle Scholar
  37. 37.
    Granit RZ, Slyper M, Ben-Porath I (2014) Axes of differentiation in breast cancer: untangling stemness, lineage identity, and the epithelial to mesenchymal transition. Wiley Interdiscip Rev Syst Biol Med 6(1):93–106CrossRefPubMedGoogle Scholar
  38. 38.
    Zomer A, Ellenbroek SI, Ritsma L, Beerling E, Vrisekoop N, Van Rheenen J (2013) Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cells 31(3):602–606CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163(5):2113–2126CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  1. 1.Department of BiotechnologyUniversity of RijekaRijekaCroatia

Personalised recommendations