Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer

Oncogene volume 30, pages 4399–4409 (2011)Cite this article

Subjects

Abstract

Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a+ cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a+ cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

K6:

keratin 6

tva:

tumor virus A

MMTV:

mouse mammary tumor virus

PyMT:

polyoma middle T antigen

αSMA:

α smooth muscle actin

RCAS:

replication competent

ALV-LTR:

splice acceptor, Bryan-RSV pol, subgroup A virus

References

  • Andrechek ER, Hardy WR, Laing MA, Muller WJ . (2004). Germ-line expression of an oncogenic erbB2 allele confers resistance to erbB2-induced mammary tumorigenesis. Proc Natl Acad Sci USA 101: 4984–4989.

    Article  CAS  Google Scholar 

  • Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC et al. (2007). Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9: 201–209.

    Article  CAS  Google Scholar 

  • Badders NM, Goel S, Clark RJ, Klos KS, Kim S, Bafico A et al. (2009). The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS One 4: e6594.

    Article  Google Scholar 

  • Bai L, Rohrschneider LR . (2010). s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue. Genes Dev 24: 1882–1892.

    Article  CAS  Google Scholar 

  • Bates P, Young JA, Varmus HE . (1993). A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor. Cell 74: 1043–1051.

    Article  CAS  Google Scholar 

  • Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI et al. (2002). Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci USA 99: 6967–6972.

    Article  CAS  Google Scholar 

  • Dilworth SM . (2002). Polyoma virus middle T antigen and its role in identifying cancer-related molecules. Nat Rev Cancer 2: 951–956.

    Article  CAS  Google Scholar 

  • Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al. (2003). in vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17: 1253–1270.

    Article  CAS  Google Scholar 

  • Du Z, Podsypanina K, Huang H, McGrath A, Toneff MJ, Bogoslovskaia E et al. (2006). Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci USA 103: 17396–17401.

    Article  CAS  Google Scholar 

  • Fisher GH, Orsulic S, Holland E, Hively WP, Li Y, Lewis BC et al. (1999). Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 18: 5253–5260.

    Article  CAS  Google Scholar 

  • Grimm SL, Bu W, Longley MA, Roop DR, Li Y, Rosen JM . (2006). Keratin 6 is not essential for mammary gland development. Breast Cancer Res 8: R29.

    Article  Google Scholar 

  • Henry MD, Triplett AA, Oh KB, Smith GH, Wagner KU . (2004). Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice. Oncogene 23: 6980–6985.

    Article  CAS  Google Scholar 

  • Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z et al. (2007). Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8: R76.

    Article  Google Scholar 

  • Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA et al. (2007). EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 8: 258.

    Article  Google Scholar 

  • Hughes SH . (2004). The RCAS vector system. Folia Biol (Praha) 50: 107–119.

    CAS  Google Scholar 

  • Ince TA, Richardson AL, Bell GW, Saitoh M, Godar S, Karnoub AE et al. (2007). Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12: 160–170.

    Article  CAS  Google Scholar 

  • Jeselsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C et al. (2010). Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell 17: 65–76.

    Article  CAS  Google Scholar 

  • Li Y, Rosen JM . (2005). Stem/progenitor cells in mouse mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 10: 17–24.

    Article  Google Scholar 

  • Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X et al. (2003). Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA 100: 15853–15858.

    Article  CAS  Google Scholar 

  • Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH et al. (2009). Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15: 907–913.

    Article  CAS  Google Scholar 

  • Lindvall C, Bu W, Williams BO, Li Y . (2007). Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 3: 157–168.

    Article  CAS  Google Scholar 

  • Mollet M, Godoy-Silva R, Berdugo C, Chalmers JJ . (2008). Computer simulations of the energy dissipation rate in a fluorescence-activated cell sorter: implications to cells. Biotechnol Bioeng 100: 260–272.

    Article  CAS  Google Scholar 

  • Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R et al. (2010). BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7: 403–417.

    Article  CAS  Google Scholar 

  • Rosner A, Miyoshi K, Landesman-Bollag E, Xu X, Seldin DC, Moser AR et al. (2002). Pathway pathology: histological differences between ErbB/Ras and Wnt pathway transgenic mammary tumors. Am J Pathol 161: 1087–1097.

    Article  CAS  Google Scholar 

  • Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML et al. (2006). Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88.

    Article  CAS  Google Scholar 

  • 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 8: R7.

    Article  Google Scholar 

  • Smith GH, Mehrel T, Roop DR . (1990). Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. Cell Growth Differ 1: 161–170.

    CAS  PubMed  Google Scholar 

  • Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D et al. (2006). Purification and unique properties of mammary epithelial stem cells. Nature 439: 993–997.

    Article  CAS  Google Scholar 

  • Toneff M, Du Z, Dong J, Huang J, Sinai P, Forman J et al. (2010). Somatic expression of PyMT or activated ErbB2 induces estrogen-independent mammary tumorigenesis. Neoplasia 12: 718–726.

    Article  CAS  Google Scholar 

  • Vaillant F, Asselin-Labat ML, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE . (2008). The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 68: 7711–7717.

    Article  CAS  Google Scholar 

  • Vargo-Gogola T, Rosen JM . (2007). Modelling breast cancer: one size does not fit all. Nat Rev Cancer 7: 659–672.

    Article  CAS  Google Scholar 

  • Visvader JE . (2011). Cells of origin in cancer. Nature 469: 314–322.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Wojcik SM, Longley MA, Roop DR . (2001). Discovery of a novel murine keratin 6 (K6) isoform explains the absence of hair and nail defects in mice deficient for K6a and K6b. J Cell Biol 154: 619–630.

    Article  CAS  Google Scholar 

  • 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: 568–577.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Tammy Tong, Amanda McGrath, Ekaterina Bogoslovskaia, Andrei Lazarev, Meghali Goswami and Yiqun Zhang for technical assistance, Drs Jeffrey Rosen and Michael Lewis for stimulating discussions and/or critical review of this manuscript, as well as Drs Robert D Cardiff and Barry Gusterson for advice on pathological comparisons. This work was supported in part by funds from USAMRMC BC030755 and BC073703 (to YL), National Institutes of Health CA113869 and CA124820 (to YL), Project 5 of MMHCC U01 CA084243-07 (to YL; U01 PI: Dr Jeffrey Rosen) and a developmental project of NCI P50 CA058183 (to YL; SPORE PI: Dr C Kent Osborne).

Author information

Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    W Bu, G D Morrison, J Huang, G C Chamness, S G Hilsenbeck & Y Li

  2. Dermatology and Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver, Aurora, CO, USA

    J Chen, D R Roop & Y Li

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    S Huang & Y Li

  4. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    S Huang, C J Creighton & S G Hilsenbeck

  5. Department of Laboratory Medicine and Medicine, University of California, San Francisco, CA, USA

    A D Leavitt

Authors
  1. W Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G D Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C J Creighton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G C Chamness
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S G Hilsenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D R Roop
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A D Leavitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Li.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bu, W., Chen, J., Morrison, G. et al. Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer. Oncogene 30, 4399–4409 (2011). https://doi.org/10.1038/onc.2011.147

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.147

Keywords

This article is cited by

Search

Advanced search

Quick links