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Progestin-regulated luminal cell and myoepithelial cell-specific responses in mammary organoid culture. 2008

Sandra Z Haslam, and Alexis Drolet, and Kyle Smith, and May Tan, and Mark Aupperlee
Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA. shaslam@msu.edu

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 17beta-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-kappaB 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.

UI MeSH Term Description Entries
D008321 Mammary Glands, Animal MAMMARY GLANDS in the non-human MAMMALS. Mammae,Udder,Animal Mammary Glands,Animal Mammary Gland,Mammary Gland, Animal,Udders
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D009924 Organ Culture Techniques A technique for maintenance or growth of animal organs in vitro. It refers to three-dimensional cultures of undisaggregated tissue retaining some or all of the histological features of the tissue in vivo. (Freshney, Culture of Animal Cells, 3d ed, p1) Organ Culture,Culture Technique, Organ,Culture Techniques, Organ,Organ Culture Technique,Organ Cultures
D009940 Organoids An organization of cells into an organ-like structure. Organoids can be generated in culture, e.g., self-organized three-dimensional tissue structures derived from STEM CELLS (see MICROPHYSIOLOGICAL SYSTEMS). They are also found in certain NEOPLASMS. Organoid
D011372 Progestins Compounds that interact with PROGESTERONE RECEPTORS in target tissues to bring about the effects similar to those of PROGESTERONE. Primary actions of progestins, including natural and synthetic steroids, are on the UTERUS and the MAMMARY GLAND in preparation for and in maintenance of PREGNANCY. Gestagenic Agent,Progestagen,Progestagenic Agent,Progestational Agent,Progestational Compound,Progestational Hormone,Progestogen,Progestogens,Gestagen,Gestagen Effect,Gestagen Effects,Gestagenic Agents,Gestagenic Effect,Gestagenic Effects,Gestagens,Progestagenic Agents,Progestagens,Progestational Agents,Progestational Compounds,Progestational Hormones,Progestin,Progestin Effect,Progestin Effects,Progestogen Effect,Progestogen Effects,Agent, Gestagenic,Agent, Progestagenic,Agent, Progestational,Compound, Progestational,Effect, Gestagen,Effect, Gestagenic,Effect, Progestin,Effect, Progestogen,Effects, Gestagen,Effects, Gestagenic,Effects, Progestin,Effects, Progestogen,Hormone, Progestational
D011397 Promegestone A synthetic progestin which is useful for the study of progestin distribution and progestin tissue receptors, as it is not bound by transcortin and binds to progesterone receptors with a higher association constant than progesterone. 17,21-Dimethyl-19-nor-4,9-pregnadiene-3,20-dione,Promestone,R-5020,R5020,RU-5020,RU5020,Surgestone,R 5020,RU 5020
D011980 Receptors, Progesterone Specific proteins found in or on cells of progesterone target tissues that specifically combine with progesterone. The cytosol progesterone-receptor complex then associates with the nucleic acids to initiate protein synthesis. There are two kinds of progesterone receptors, A and B. Both are induced by estrogen and have short half-lives. Progesterone Receptors,Progestin Receptor,Progestin Receptors,Receptor, Progesterone,Receptors, Progestin,Progesterone Receptor,Receptor, Progestin
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004338 Drug Combinations Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. Drug Combination,Combination, Drug,Combinations, Drug
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell

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