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.

Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

“…It is possible that mifepristone may reduce cancer development by upregulation of inhibitory factors such as TGF-b1 and/or downregulation of stimulatory pathways including IGF. Progesterone and IGF increase ductal elongation in the mammary gland (Ruan et al, 2005) and progesterone and the PR-B isoform has been shown to increase insulin receptor substrate-2 expression (Vassen et al, 1999;Cui et al, 2003). One can speculate that the enhanced ductal elongation observed in the Brca1-deficient mice was secondary to increased PR and IGF signaling in the pubertal mice.…”

Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2

“…A role for IGF-1 in the branching we have described cannot be eliminated. Indeed, Ruan et al (2005) have shown that in the absence of E, IGF-1 and P act synergistically to develop the branched ductal tree. During branching, IGF-1 and E (Zhang et al, 2002) act indirectly on the epithelium through the stroma while our data indicate that P acts directly on the epithelium.…”

Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia

“…Negative controls for pYIRS-1 identification were incubated with primary antibody preabsorbed with 200-fold molar excess of the pYIRS-1 phospho-peptide. As previously published, antibody specificity for pYIRS-1 was also determined by Western blotting of MCF-7 cell proteins [9]. Omission of the primary antibody and replacement with non-immune IgG was used as a negative control for Ki67 staining.…”

“…We reported that GH-stimulated IGF-I was essential for mammary development [5][6][7]. IGF-I, in fact, mediates the known effects of GH in mammary development [8], and is also required for E 2 and progesterone action (singly or together) [9]. Inhibition of IGF-I action by IGF-I binding protein (IGFBP)1 and IGFBP5 has also been shown to prevent mammary development [10,11].…”