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Submitted on October 15, 2004
Accepted on December 1, 2004
Neuroendocrine Unit, Departments of Medicineand Physiology, New York University School of Medicine, and DVA Medical Center, 550 First Avenue, New York, NY 10016
* To whom correspondence should be addressed. 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 anti-apoptotic 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 (TEBs) formation and side branching (P < 0.002). In contrast to previous findings, long-term exposure to E2 alone, without IGF-I, caused formation ducts and side branches, a novel finding. Both IGF-I and E2 were found necessary for Pg-induced alveolar development. In conclusion 1) Pg, through PgR can enhance IGF-I action in DM; E2 acts through a similar mechanism, 2) E2 alone caused formation of ducts and side branches, 3) there were differences in the actions of Pg and E2, the former largely affecting duct formation and extension, and the latter side branching, and 4) both IGF-I and E2 were necessary in order for Pg to form mature alveoli.
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