Progesterone induces adult mammary stem cell expansion
Top Cited Papers
- 10 June 2010
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 465 (7299), 803-807
- https://doi.org/10.1038/nature09091
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.Keywords
This publication has 30 references indexed in Scilit:
- Two distinct mechanisms underlie progesterone-induced proliferation in the mammary glandProceedings of the National Academy of Sciences, 2010
- The Wnt Receptor, Lrp5, Is Expressed by Mouse Mammary Stem Cells and Is Required to Maintain the Basal LineagePLOS ONE, 2009
- DNA Replication Licensing and Progenitor Numbers Are Increased by Progesterone in Normal Human BreastEndocrinology, 2009
- Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiationNature, 2006
- Prevention of Brca1 -Mediated Mammary Tumorigenesis in Mice by a Progesterone AntagonistScience, 2006
- Steroid Hormone Receptor Status of Mouse Mammary Stem CellsJNCI Journal of the National Cancer Institute, 2006
- Generation of a functional mammary gland from a single stem cellNature, 2006
- Purification and unique properties of mammary epithelial stem cellsNature, 2006
- Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled TrialJAMA, 2002
- Cellular Turnover in the Mammary Gland Is Correlated with Systemic Levels of Progesterone and Not 17β-Estradiol During the Estrous Cycle1Biology of Reproduction, 2001