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Progesterone induces adult mammary stem cell expansion

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

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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.

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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.

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Change history

  • 10 June 2010

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

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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.

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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

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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.

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Correspondence to Rama Khokha.

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The authors declare no competing financial interests.

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

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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

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