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.

  • Letter
  • Published:

Progesterone induces adult mammary stem cell expansion

Nature volume 465, pages 803–807 (2010)Cite this article

Subjects

This article has been updated

Abstract

Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density1,2. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown3,4,5. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation6. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: MaSCs fluctuate during the reproductive cycle.
Figure 2: Progesterone drives expansion of the MaSC-enriched subpopulation in vivo.
Figure 3: Dynamic mammary cell turnover in cycling females whereas stem-cell-enriched basal cells show stasis in aged mice.
Figure 4: RANKL and Wnt4 as paracrine effectors of progesterone-induced MaSC expansion.

Similar content being viewed by others

Change history

  • 10 June 2010

    Minor corrections were made to affiliation 2 and Fig. 2a, c, d.

References

  1. Veronesi, U., Boyle, P., Goldhirsch, A., Orecchia, R. & Viale, G. Breast cancer. Lancet 365, 1727–1741 (2005)

    Article  Google Scholar 

  2. Kelsey, J. L., Gammon, M. D. & John, E. M. Reproductive factors and breast cancer. Epidemiol. Rev. 15, 36–47 (1993)

    Article  CAS  Google Scholar 

  3. Bernstein, L. Epidemiology of endocrine-related risk factors for breast cancer. J. Mammary Gland Biol. Neoplasia 7, 3–15 (2002)

    Article  Google Scholar 

  4. Trichopoulos, D., MacMahon, B. & Cole, P. Menopause and breast cancer risk. J. Natl Cancer Inst. 48, 605–613 (1972)

    CAS  PubMed  Google Scholar 

  5. Apter, D., Reinila, M. & Vihko, R. Some endocrine characteristics of early menarche, a risk factor for breast cancer, are preserved into adulthood. Int. J. Cancer 44, 783–787 (1989)

    Article  CAS  Google Scholar 

  6. Brisken, C. & Duss, S. Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspective. Stem Cell Rev. 3, 147–156 (2007)

    Article  CAS  Google Scholar 

  7. Harmes, D. C. & DiRenzo, J. Cellular quiescence in mammary stem cells and breast tumor stem cells: got testable hypotheses? J. Mammary Gland Biol. Neoplasia 14, 19–27 (2009)

    Article  Google Scholar 

  8. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006)

    Article  CAS  ADS  Google Scholar 

  9. Smith, G. H. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 132, 681–687 (2005)

    Article  CAS  Google Scholar 

  10. Fata, J. E., Chaudhary, V. & Khokha, R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17β-estradiol during the estrous cycle. Biol. Reprod. 65, 680–688 (2001)

    Article  CAS  Google Scholar 

  11. Graham, J. D. & Clarke, C. L. Physiological action of progesterone in target tissues. Endocr. Rev. 18, 502–519 (1997)

    CAS  PubMed  Google Scholar 

  12. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006)

    Article  CAS  ADS  Google Scholar 

  13. Daniel, C. W., Silberstein, G. B. & Strickland, P. Direct action of 17β-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res. 47, 6052–6057 (1987)

    CAS  PubMed  Google Scholar 

  14. Beleut, M. et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc. Natl Acad. Sci. USA 107, 2989–2994 (2010)

    Article  CAS  ADS  Google Scholar 

  15. Haslam, S. Z. & Shyamala, G. Effect of oestradiol on progesterone receptors in normal mammary glands and its relationship with lactation. Biochem. J. 182, 127–131 (1979)

    Article  CAS  Google Scholar 

  16. Asselin-Labat, M. L. et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nature Cell Biol. 9, 201–209 (2007)

    Article  CAS  Google Scholar 

  17. Chepko, G. & Smith, G. H. Mammary epithelial stem cells: our current understanding. J. Mammary Gland Biol. Neoplasia 4, 35–52 (1999)

    Article  CAS  Google Scholar 

  18. Petersen, O. W., Ronnov-Jessen, L., Howlett, A. R. & Bissell, M. J. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc. Natl Acad. Sci. USA 89, 9064–9068 (1992)

    Article  CAS  ADS  Google Scholar 

  19. Asselin-Labat, M. L. et al. Steroid hormone receptor status of mouse mammary stem cells. J. Natl Cancer Inst. 98, 1011–1014 (2006)

    Article  CAS  Google Scholar 

  20. Mote, P. A. et al. Overlapping and distinct expression of progesterone receptors A and B in mouse uterus and mammary gland during the estrous cycle. Endocrinology 147, 5503–5512 (2006)

    Article  CAS  Google Scholar 

  21. Kariagina, A., Aupperlee, M. D. & Haslam, S. Z. Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 148, 2723–2736 (2007)

    Article  CAS  Google Scholar 

  22. Mulac-Jericevic, B., Lydon, J. P., DeMayo, F. J. & Conneely, O. M. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc. Natl Acad. Sci. USA 100, 9744–9749 (2003)

    Article  CAS  ADS  Google Scholar 

  23. Brisken, C. et al. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl Acad. Sci. USA 95, 5076–5081 (1998)

    Article  CAS  ADS  Google Scholar 

  24. Brisken, C. et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev. 14, 650–654 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Fata, J. E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000)

    Article  CAS  Google Scholar 

  26. Badders, N. M. et al. The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS ONE 4, e6594 (2009)

    Article  ADS  Google Scholar 

  27. Graham, J. D. et al. DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. Endocrinology 150, 3318–3326 (2009)

    Article  CAS  Google Scholar 

  28. Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J. Am. Med. Assoc. 288, 321–333 (2002)

    Article  CAS  Google Scholar 

  29. Lydon, J. P., Ge, G., Kittrell, F. S., Medina, D. & O’Malley, B. W. Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res. 59, 4276–4284 (1999)

    CAS  Google Scholar 

  30. Poole, A. J. et al. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314, 1467–1470 (2006)

    Article  CAS  ADS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Canadian Breast Cancer Research Alliance. P.A.J. holds a Terry Fox Foundation studentship through an award from the National Cancer Institute of Canada; H.W.J. holds a studentship and A.G.B. a fellowship from the Canadian Breast Cancer Foundation, Ontario. The authors thank F. Tong and R. Nayyar of the OCI FACS facility for cell sorting, and M. Monroy and S. Yousef of the UHN Animal Resources Center for performing ovariectomies.

Author information

Authors and Affiliations

  1. Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, Toronto M5G 2M9, Ontario, Canada,

    Purna A. Joshi, Hartland W. Jackson, Alexander G. Beristain, Marco A. Di Grappa, Paul D. Waterhouse & Rama Khokha

  2. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales 2145, Australia ,

    Patricia A. Mote & Christine L. Clarke

  3. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK

    John Stingl

Authors
  1. Purna A. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hartland W. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander G. Beristain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco A. Di Grappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patricia A. Mote
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christine L. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Stingl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul D. Waterhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rama Khokha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.A.J. designed and performed majority of the experiments and data analysis; H.W.J. conducted CFC assays and contributed to transplantation experiments; A.G.B. extracted RNA and performed quantitative RT–PCR; M.A.D.G. administered hormones and designed graphics; P.M. and C.C. provided PR antibody and advice; J.S. advised on multiple aspects of stem cell analyses; P.D.W. conceptualized the importance of the reproductive cycle; and R.K. directed the study. P.A.J. and R.K. wrote the paper.

Corresponding author

Correspondence to Rama Khokha.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and References, Supplementary Table 1 and Supplementary Figures S1-S5 with legends. (PDF 10003 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joshi, P., Jackson, H., Beristain, A. et al. Progesterone induces adult mammary stem cell expansion. Nature 465, 803–807 (2010). https://doi.org/10.1038/nature09091

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09091

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer