Submitted to: Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2002
Publication Date: 8/1/2003
Citation: HOVEY, R.C., HARRIS, J., HADSELL, D., LEE, A.V., ORMANDY, C.J., VONDERHAAR, B.K. LOCAL INSULIN-LIKE GROWTH FACTOR-II MEDIATES PROLACTIN-INDUCED MAMMARY GLAND DEVELOPMENT. MOLECULAR ENDOCRINOLOGY. 2003. p. 460-471. Interpretive Summary: Mammary gland development is a dynamic process that occurs at specific stages during postnatal development and is coordinately regulated by key hormones and locally derived growth factors. Of the hormones known to regulate the mammary gland, the pituitary-derived hormone prolactin (PRL) is a primary factor in the pregnancy-dependent preparation of the mammary epithelium for lactation. The growth factor insulin like growth factor II (IGF-II) has been implicated as a locally derived growth factor involved with mammary gland development The studies described in this paper evaluated the hypothesis that IGF-II is a locally derived mediator of PRL action within the mammary gland. These studies found that expression of IGF-II within the mammary glands of mice was dependent on the receptor for PRL. They also demonstrated that expression of the IGF-II gene in culture mammary cells could be induced by PRL and that the induction of IGF-II gene expression coincided with induction of a key IGF-II signaling protein, insulin receptor substrate 1. The study findings provide important new knowledge giving scientists a better understanding of the mechanisms underlying normal and abnormal breast cell behavior and development, and could provide information ultimately leading toward improvements in the prevention and treatment of breast cancer or in the treatment of lactational insufficiency.
Technical Abstract: Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II. During sexual maturity and in early pregnancy, the level of IGF-II mRNA in the mammary gland was increased concurrent with increased PRL receptor expression. The level of IGF-II mRNA was reduced in mammary tissue from PRL receptor-/- mice during early pregnancy, and explants of mouse mammary gland and HC11 mammary epithelial cells both increased their expression of IGF-II after exposure to PRL in vitro. These findings coincided with the demonstration that IGF-II stimulated alveolar development in mammary glands in whole organ culture. PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro. Insight into the mechanism by which PRL induced IGF-II expression was provided by the fact that it was blocked by the Jak2 inhibitor AG490 and the MAPK inhibitor PD98059. Finally, induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors. Together, these data demonstrate a role for IGF-II as a mediator of PRL action in the mouse mammary gland during ductal branching and alveolar development.