Amphiregulin-induced luminal mammary epithelial differentiation is stimulated by 2-methoxyestradiol and 17b-estradiol

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We have previously demonstrated that 2-methoxyestradiol (2ME2), a metabolite of 17b-estradiol (E2), has differentiating effects on the mammary gland (Huh et al, Endocrinology, 2007) which was associated with the up-regulation of amphiregulin (AREG). In order to more further evaluate whether 2ME2 induced differentiation of the mammary gland is mediated through AREG, wild type (wt) and AREG KO mice were supplemented with 2ME2 or E2. Both 2ME2 and E2 induced alveolar-type structural development in wt mice. AREG KO mice have been previously shown to have impaired mammary development. 2ME2 induced ductal outgrowth, while E2 mildly increased ductal branching in AREG KO mammary gland, however, 2ME2 but not E2 caused mammary epithelial cells to differentiate into casein-producing cells. Additionally, 2ME2 treatment resulted in a significant increase in cytokeratin 8-positive luminal epithelial cells in WT mammary glands compared to the effect of E2, but luminal expansion by 2ME2 was dramatically reduced in AREG KO mammary glands. These results are consistent with our analyses of publicly available gene expression profiling data, where AREG expression is associated with luminal types of breast cancer, but not basal types of breast cancer. AREG appears to play an important role in cell-lineage differentiation of normal and tumorigenic mammary epithelial cells.
 We conclude that 2ME2-induced differentiation in mammary gland is distinct from E2 and requires AREG for luminal cell-lineage development and a potential application in subtype specific breast cancers in patients.