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Control of mammary stem cell function by steroid hormone signalling

Abstract

The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk1,2,3, underpinning the benefit of endocrine therapies in the treatment of breast cancer4. Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence5,6. Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term7. The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs)8,9 are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors10. Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.

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Figure 1: Steroid hormone deprivation reduces MaSC activity.
Figure 2: Marked increase in the number of MaSCs in mid-pregnancy.
Figure 3: RANKL is involved in MaSC activation observed during pregnancy.

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Primary accessions

Gene Expression Omnibus

Data deposits

All microarray data are available from the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo) under accession codes GSE20401 and GSE20402.

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Acknowledgements

We are grateful to A. Morcom and T. Ward for technical assistance, T. Bouras for advice, S. Mihajlovic for histology and F. Battye for FACS support. We thank C. Clarke for providing the hPRa7 antibody, A. Burgess for AG1478, A. Parlow for prolactin, and the Australian Genome Research Facility for RNA bioanalyses. M.-L.A.-L. is supported by an Australian Research Council Postdoctoral Fellowship. This work was supported by the Victorian Breast Cancer Research Consortium (J.E.V. and G.J.L.), the National Health and Medical Research Council (Australia), the Susan G. Komen Foundation, the National Breast Cancer Foundation and the Australian Cancer Research Foundation.

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Authors and Affiliations

Authors

Contributions

M.-L.A.-L. conceptualized and designed the experiments and performed most of the experiments and data analysis; F.V. performed transplantation experiments and analysis; J.S. performed in vitro inhibitor experiments; B.P. performed quantitative RT–PCR; D.W. and G.K.S. performed bioinformatics analyses; E.R.S. provided ArKO mice and advice; H.Y. provided anti-RANKL inhibitor and advice; T.J.M. provided advice and helped design RANKL experiments; J.E.V. and G.J.L. conceived and directed the study, and J.E.V., G.J.L. and M.-L.A.-L. wrote the manuscript.

Corresponding authors

Correspondence to Geoffrey J. Lindeman or Jane E. Visvader.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S7 with legends. The Supplementary Tables were added on 14 April 2010. A small correction was made to Supplementary Table 5 on 19 May 2010. (PDF 2300 kb)

Supplementary Table 1

This file contains the gene profiling data (Log2-intensity and the log2-fold-change) for mammary populations from control versus ovariectomized (Ovx) and 12.5 day pregnant mice. (XLS 623 kb)

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Asselin-Labat, ML., Vaillant, F., Sheridan, J. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010). https://doi.org/10.1038/nature09027

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