Progestin-Regulated Luminal Cell and Myoepithelial Cell-Specific Responses in Mammary Organoid Culture
Open Access
- 24 January 2008
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 149 (5), 2098-2107
- https://doi.org/10.1210/en.2007-1398
Abstract
Normal mammary gland development requires the coordinated proliferation and morphogenesis of both mammary luminal epithelial cells (LECs) and myoepithelial cells (MECs). Cell proliferation in cultured mammary organoids containing both LECs and MECs is not increased by progestin (R5020) or 17β-estradiol (E2) alone or R5020+E2 but is increased by E2-regulated, mammary stroma-derived Hepatocyte growth factor (HGF) and further increased by HGF+R5020. We investigated the effects of HGF and/or R5020 on morphology and LEC- and MEC-specific in vitro proliferation in organoids. HGF-induced tubulogenesis was initiated and carried out by LECs starting with cellular extensions, followed by the formation of chains and cords, and culminating in tubule formation. MECs did not appear to have an active role in this process. Whereas HGF by itself caused maximal proliferation of LECs, HGF+R5020 produced a synergistic and specific increase in MEC proliferation. Because only LECs expressed progesterone receptors (PRs), we investigated the role of receptor activator of nuclear factor-κB ligand (RANKL), a progestin-induced paracrine factor, in mediating increased MEC proliferation. Quantitative RT-PCR showed that RANKL mRNA was induced by R5020 or HGF+R5020 and RANKL protein colocalized with PRs in LECs. The increased proliferation of MECs in response to HGF+R5020 could be blocked by neutralizing antibody to RANKL and reproduced by treatment with HGF plus exogenous RANKL in place of R5020. Neither R5020, nor exogenously administered RANKL increased proliferation of LECs. These results led us to conclude that RANKL, induced by progestin in PR-positive cells, is secreted and interacts with HGF to specifically increase proliferation of PR-negative MECs.Keywords
This publication has 35 references indexed in Scilit:
- Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2Oncogene, 2007
- RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial AciniMolecular and Cellular Biology, 2007
- Amelioration of bone loss in collagen-induced arthritis by neutralizing anti-RANKL monoclonal antibodyBiochemical and Biophysical Research Communications, 2006
- Myoepithelial Cells: Their Origin and Function in Breast Morphogenesis and NeoplasiaJournal of Mammary Gland Biology and Neoplasia, 2005
- Signals Which Build a TubuleNephron Experimental Nephrology, 2005
- IKKα Provides an Essential Link between RANK Signaling and Cyclin D1 Expression during Mammary Gland DevelopmentCell, 2001
- Desmosomal adhesion regulates epithelial morphogenesis and cell positioningNature, 2001
- Hepatocyte growth factor/scatter factor‐induced intracellular signallingInternational Journal of Experimental Pathology, 2000
- In VivoEffects of Hepatocyte Growth Factor/Scatter Factor on Mouse Mammary Gland DevelopmentExperimental Cell Research, 1998
- The ontogeny and cellular distribution of estrogen receptors in normal mouse mammary glandThe Journal of Steroid Biochemistry and Molecular Biology, 1992