Progesterone and Wnt4 Control Mammary Stem Cells Via Myoepithelial Crosstalk

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2015 Jan 22

PMID 25603931

Citations 67

Authors

Renuga Devi Rajaram

Duje Buric

Marian Caikovski

Ayyakkannu Ayyanan

Jacques Rougemont

Jingdong Shan

Seppo J Vainio

Ozden Yalcin-Ozuysal

Cathrin Brisken

Affiliations

Soon will be listed here.

Abstract

Ovarian hormones increase breast cancer risk by poorly understood mechanisms. We assess the role of progesterone on global stem cell function by serially transplanting mouse mammary epithelia. Progesterone receptor (PR) deletion severely reduces the regeneration capacity of the mammary epithelium. The PR target, receptor activator of Nf-κB ligand (RANKL), is not required for this function, and the deletion of Wnt4 reduces the mammary regeneration capacity even more than PR ablation. A fluorescent reporter reveals so far undetected perinatal Wnt4 expression that is independent of hormone signaling. Pubertal and adult Wnt4 expression is specific to PR+ luminal cells and requires intact PR signaling. Conditional deletion of Wnt4 reveals that this early, previously unappreciated, Wnt4 expression is functionally important. We provide genetic evidence that canonical Wnt signaling in the myoepithelium required PR and Wnt4, whereas the canonical Wnt signaling activities observed in the embryonic mammary bud and in the stroma around terminal end buds are independent of Wnt4. Thus, progesterone and Wnt4 control stem cell function through a luminal-myoepithelial crosstalk with Wnt4 acting independent of PR perinatally.

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References

Shan J, Jokela T, Skovorodkin I, Vainio S . Mapping of the fate of cell lineages generated from cells that express the Wnt4 gene by time-lapse during kidney development. Differentiation. 2009; 79(1):57-64. DOI: 10.1016/j.diff.2009.08.006. View

Caligioni C . Assessing reproductive status/stages in mice. Curr Protoc Neurosci. 2009; Appendix 4:Appendix 4I. PMC: 2755182. DOI: 10.1002/0471142301.nsa04is48. View

Stark K, Vainio S, Vassileva G, McMahon A . Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994; 372(6507):679-83. DOI: 10.1038/372679a0. View

Tanos T, Brisken C . What signals operate in the mammary niche?. Breast Dis. 2008; 29:69-82. DOI: 10.3233/bd-2008-29108. View

Arial Zeng Y, Nusse R . Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell. 2010; 6(6):568-77. PMC: 2917779. DOI: 10.1016/j.stem.2010.03.020. View

Molyneux G, Geyer F, Magnay F, McCarthy A, Kendrick H, Natrajan R . BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010; 7(3):403-17. DOI: 10.1016/j.stem.2010.07.010. View

Muzumdar M, Tasic B, Miyamichi K, Li L, Luo L . A global double-fluorescent Cre reporter mouse. Genesis. 2007; 45(9):593-605. DOI: 10.1002/dvg.20335. View

Lydon J, Demayo F, FUNK C, Mani S, Hughes A, Montgomery Jr C . Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995; 9(18):2266-78. DOI: 10.1101/gad.9.18.2266. View

Kessenbrock K, Dijkgraaf G, Lawson D, Littlepage L, Shahi P, Pieper U . A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway. Cell Stem Cell. 2013; 13(3):300-13. PMC: 3769456. DOI: 10.1016/j.stem.2013.06.005. View

10.

Phippard D, Niemeyer C, Dale T . Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation. 1994; 57(3):205-14. DOI: 10.1046/j.1432-0436.1994.5730205.x. View

11.

Liu B, McDermott S, Khwaja S, Alexander C . The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci U S A. 2004; 101(12):4158-63. PMC: 384711. DOI: 10.1073/pnas.0400699101. View

12.

Chu E, Hens J, Andl T, Kairo A, Yamaguchi T, Brisken C . Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development. 2004; 131(19):4819-29. DOI: 10.1242/dev.01347. View

13.

Haslam S, Shyamala G . Effect of oestradiol on progesterone receptors in normal mammary glands and its relationship with lactation. Biochem J. 1979; 182(1):127-31. PMC: 1161241. DOI: 10.1042/bj1820127. View

14.

Heinonen K, Vanegas J, Lew D, Krosl J, Perreault C . Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. PLoS One. 2011; 6(4):e19279. PMC: 3082562. DOI: 10.1371/journal.pone.0019279. View

15.

Cai C, Yu Q, Jiang W, Liu W, Song W, Yu H . R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal. Genes Dev. 2014; 28(20):2205-18. PMC: 4201283. DOI: 10.1101/gad.245142.114. View

16.

Shan J, Jokela T, Peltoketo H, Vainio S . Generation of an allele to inactivate Wnt4 gene function conditionally in the mouse. Genesis. 2009; 47(11):782-8. DOI: 10.1002/dvg.20566. View

17.

Joshi P, Jackson H, Beristain A, Di Grappa M, Mote P, Clarke C . Progesterone induces adult mammary stem cell expansion. Nature. 2010; 465(7299):803-7. DOI: 10.1038/nature09091. View

18.

Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey S . Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev. 2000; 14(6):650-4. PMC: 316462. View

19.

Clarke R, Howell A, Potten C, Anderson E . Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 1997; 57(22):4987-91. View

20.

Rios A, Fu N, Lindeman G, Visvader J . In situ identification of bipotent stem cells in the mammary gland. Nature. 2014; 506(7488):322-7. DOI: 10.1038/nature12948. View