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.

  • Short Communication
  • Published:

The PR status of the originating cell of ER/PR-negative mouse mammary tumors

Oncogene volume 35, pages 4149–4154 (2016)Cite this article

Subjects

Abstract

Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an oncogene (ErbB2) and a floxed green fluorescent protein (GFP) in PRCre/+mice, whose Cre gene is under the control of the PR promoter, we were able to trace the PR status of the infected cells as they progressed to cancer. We found that the resulting early lesions stained negative for PR in most of the cells and usually retained GFP. The resulting tumors lacked ER and PR, and 75% (15/20) of them retained the GFP signal in all tumor cells, suggesting PR was never expressed throughout the evolution of a majority of these tumors. In conclusion, our data demonstrate that ErbB2-initiated ER/PR-negative mammary tumors primarily originate from the subset of the mammary epithelium that is negative for PR and probably ER as well. These findings also provide an explanation for why antihormonal therapy fails to prevent ER-negative breast cancers.

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

References

  1. Clarke RB, Howell A, Potten CS, Anderson E . Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 1997; 57: 4987–4991.

    CAS  Google Scholar 

  2. Zeps N, Bentel JM, Papadimitriou JM, D'Antuono MF, Dawkins HJ . Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth. Differentiation 1998; 62: 221–226.

    Article  CAS  Google Scholar 

  3. Mallepell S, Krust A, Chambon P, Brisken C . Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci USA 2006; 103: 2196–2201.

    Article  CAS  Google Scholar 

  4. Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP et al. Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol 1999; 155: 1811–1815.

    Article  CAS  Google Scholar 

  5. Haricharan S, Hein SM, Dong J, Toneff MJ, Aina OH, Rao PH et al. Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer. Oncogene 2013; 33: 5729–5739.

    Article  Google Scholar 

  6. Harvey JM, Clark GM, Osborne CK, Allred DC . Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474–1481.

    Article  CAS  Google Scholar 

  7. Allred DC, Mohsin SK, Fuqua SA . Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 2001; 8: 47–61.

    Article  CAS  Google Scholar 

  8. Allred DC, Brown P, Medina D . The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer. Breast Cancer Res 2004; 6: 240–245.

    Article  CAS  Google Scholar 

  9. Dontu G, El-Ashry D, Wicha MS . Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab 2004; 15: 193–197.

    Article  CAS  Google Scholar 

  10. Gusterson BA, Machin LG, Gullick WJ, Gibbs NM, Powles TJ, Elliott C et al. c-erbB-2 expression in benign and malignant breast disease. Br J Cancer 1988; 58: 453–457.

    Article  CAS  Google Scholar 

  11. Edorh A, Leroux A, N'Sossani B, Parache RM, Rihn B . Detection by immunohistochemistry of c-erbB2 oncoprotein in breast carcinomas and benign mammary lesions. Cell Mol Biol 1999; 45: 831–840.

    CAS  PubMed  Google Scholar 

  12. Aubele M, Werner M, Hofler H . Genetic alterations in presumptive precursor lesions of breast carcinomas. Anal Cell Pathol 2002; 24: 69–76.

    Article  CAS  Google Scholar 

  13. Heffelfinger SC, Yassin R, Miller MA, Lower EE . Cyclin D1, retinoblastoma, p53, and Her2/neu protein expression in preinvasive breast pathologies: correlation with vascularity. Pathobiology 2000; 68: 129–136.

    Article  CAS  Google Scholar 

  14. Bu W, Xin L, Toneff M, Li L, Li Y . Lentivirus vectors for stably introducing genes into mammary epithelial cells in vivo. J Mammary Gland Biol Neoplasia 2009; 14: 401–404.

    Article  Google Scholar 

  15. Du Z, Li Y . RCAS-TVA in the mammary gland: an in vivo oncogene screen and a high fidelity model for breast transformation? Cell Cycle 2007; 6: 823–826.

    Article  CAS  Google Scholar 

  16. Reddy JP, Li Y . The RCAS-TVA system for introduction of oncogenes into selected somatic mammary epithelial cells in vivo. J Mammary Gland Biol Neoplasia 2009; 14: 405–409.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Fendrick JL, Raafat AM, Haslam SZ . Mammary gland growth and development from the postnatal period to postmenopause: ovarian steroid receptor ontogeny and regulation in the mouse. J Mammary Gland Biol Neoplasia 1998; 3: 7–22.

    Article  CAS  Google Scholar 

  20. Mukherjee A, Soyal SM, Wheeler DA, Fernandez-Valdivia R, Nguyen J, DeMayo FJ et al. Targeting iCre expression to murine progesterone receptor cell-lineages using bacterial artificial chromosome transgenesis. Genesis 2006; 44: 601–610.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Bu W, Chen J, Morrison GD, Huang S, Creighton CJ, Huang J 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 2011; 30: 4399–4409.

    Article  CAS  Google Scholar 

  23. Du Z, Podsypanina K, Huang S, McGrath A, Toneff MJ, Bogoslovskaia E et al. 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 2006; 103: 17396–17401.

    Article  CAS  Google Scholar 

  24. Reddy JP, Peddibhotla S, Bu W, Zhao J, Haricharan S, Du YC et al. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proc Natl Acad Sci USA 2010; 107: 3728–3733.

    Article  CAS  Google Scholar 

  25. Siwko SK, Bu W, Gutierrez C, Lewis B, Jechlinger M, Schaffhausen B et al. Lentivirus-mediated oncogene introduction into mammary cells in vivo induces tumors. Neoplasia 2008; 10: 653–662, 1p following 62.

    Article  CAS  Google Scholar 

  26. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003; 163: 2113–2126.

    Article  Google Scholar 

  27. Haricharan S, Dong J, Hein S, Reddy JP, Du Z, Toneff M et al. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy. eLife 2013; 2: e00996.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Vidya Sinha and Sarah Hein for stimulating discussion. This work was supported in part by funds from NIH CA124820 (to YL) and U54CA149196 (to YL; PI: Stephan Wong); from CDMRP BC060332 (to YL), BC085050 (to YL) and BC073703 (to YL) and from Mary Kay Foundation (TMKF042-14 (to YL) as well as by the resources from the Lester & Sue Smith Breast Center (P50 CA186784), the Dan L. Duncan Cancer Center (P30CA125123). JD was supported by BCM SPORE career development award (P50-CA058183).

Author information

Authors and Affiliations

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

    J Dong, W Zhao, A Shi, M Toneff, D So & Y Li

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

    J Dong, M Toneff, J Lydon & Y Li

  3. Department of Breast Surgery, First Hospital of Jilin University, Changchun, China

    A Shi

  4. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

    Y Li

Authors
  1. J Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Toneff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Lydon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D So
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. 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 this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, J., Zhao, W., Shi, A. et al. The PR status of the originating cell of ER/PR-negative mouse mammary tumors. Oncogene 35, 4149–4154 (2016). https://doi.org/10.1038/onc.2015.465

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.465

This article is cited by

Search

Advanced search

Quick links