title: Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action.
abstract: Progestins have been implicated in breast cancer development, yet a role for progesterone (Pg) in ductal morphogenesis (DM) has not been established. To determine whether Pg could cause DM, we compared relative effects of Pg, estradiol (E2) and IGF-I on anatomical and molecular biological parameters of IGF-I-related DM in oophorectomized female IGF-I(-/-) mice. Pg had little independent effect on mammary development, but together with IGF-I, in the absence of E2, Pg stimulated an extensive network of branching ducts, occupying 92% of the gland vs. 28.3% with IGF-I alone, resembling pubertal development (P < 0.002). Its major effect was on enhancing duct length and branching (P < 0.002). Additionally, Pg enhanced phosphorylation of IRS-1, increased cell division, and increased the antiapoptotic effect of IGF-I. Pg action was inhibited by RU486 (P < 0.01). E2 also stimulated DM by enhancing IGF-I action but had a greater effect on terminal end bud formation and side branching (P < 0.002). In contrast to previous findings, long-term exposure to E2 alone, without IGF-I, caused formation of ducts and side branches, a novel finding. Both IGF-I and E2 were found necessary for Pg-induced alveolar development. In conclusion, Pg, through Pg receptor can enhance IGF-I action in DM, and E2 acts through a similar mechanism; E2 alone caused formation of ducts and side branches; there were differences in the actions of Pg and E2, the former largely affecting duct formation and extension, and the latter side branching; and both IGF-I and E2 were necessary for Pg to form mature alveoli.
authors.affiliation: Neuroendocrine Unit, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Ruan
authors.forename: Marie E
authors.initials: ME
authors.lastname: Monaco
authors.forename: David L
authors.initials: DL
authors.lastname: Kleinberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006728:Hormones / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D009024:Morphogenesis; D010052:Ovariectomy; D010766:Phosphorylation; D011374:Progesterone / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D006728:Hormones; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I