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Progesterone Stimulates Mammary Gland Ductal Morphogenesis by Synergizing with and Enhancing Insulin-Like Growth Factor-I Action

Neuroendocrine Unit, Departments of Medicine (W.R., D.L.K.) and Physiology (M.E.M.), New York University School of Medicine and Department of Veterans Affairs Medical Center, New York, New York 10016

Address all correspondence and requests for reprints to: David L. Kleinberg, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: david.kleinberg{at}med.nyu.edu.

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.

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