Alterations in mammary gland development following neonatal exposure to estradiol, transforming growth factor α, and estrogen receptor antagonist ICI 182,780

Leena Hilakivi-Clarke, Elizabeth Cho, Margarita Raygada, Nicholas Kenney

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

High fetal/early postnatal revels of estrogen increase breast cancer risk, but the mechanisms remain unknown. Growth factors, such as transforming growth factor or (TGFα), may participate as secondary modifiers in this process. We characterized a modulatory role of early postnatal exposure to 17β-estradiol (E2) on the developing mammary gland morphology by treating intact female CD-1 mice with physiological doses of E2 (2-4 μg), human recombinant TGFα (4 μg), or an estrogen receptor (ER) antagonist ICI 182,780 (20 μg) during postnatal days 1-3. Early postnatal exposure of E2 stimulated mammary ductal growth by days 25 and 35, but by day 50 this was inhibited. The level of differentiation from terminal end buds (TEBs) to the lobulo-alveolar units (LAUs) also was reduced by day 50. The number of TEBs was increased throughout most of the development in the female mice exposed to E2 during early life. An exposure to TGFα or ICI 182,780 between postnatal days 1 and 3 stimulated ductal growth, formation of TEBs, and the differentiation of mammary epithelial structures. ICI 182,80 treatment also caused hyperplastic lobular-like structures in 54-day-old females. Thus, neonatal exposure to TGFα and ICI 182,780 induced both similar (increase in TEBs) and different (increase/decrease in lobulo-alveolar differentiation) developmental changes in the mouse mammary gland, when compared with an exposure to E2. A unique feature of the postnatal E2 treatment was that it inhibited ductal migration by days 50-54. Our data suggest than an exposure to E2 on postnatal days 1-3, possibly combined with secondary epigenetic alterations, leads to various changes within the developing mammary tree. These changes may be potential prerequisites for mammary tumorigenesis.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalJournal of cellular physiology
Volume170
Issue number3
DOIs
StatePublished - Mar 1997
Externally publishedYes

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