유방상피 조직의 발달 및 유방암 형성에서의 Rankl-Id2의 기능 연구

Abstract

The mammary gland is a complex organ that proliferates and differentiates during puberty, pregnancy, and lactation under the influence of various hormones, including estrogen, progesterone, and prolactin. Receptor activator of NF-B ligand (Rankl) is a key factor for osteoclast differentiation/activation, dendritic cell survival, and lymphoid organogenesis. In addition to the regulation of bone remodeling and immune functions, we have previously shown that Rankl plays a critical role in mammary gland development during pregnancy. Mice lacking Rankl or its receptor, Rank, show impaired lobulo-alveolar development during pregnancy. Recent studies have reported that the pregnancy hormones, progesterone and prolactin, induce the expression of Rankl, suggesting that these lactogenic hormones regulate mammary gland development via the Rankl-Rank signaling pathway. However, how Rankl-Rank signaling regulates various aspects of proliferation, survival, and differentiation of MECs in lactating mammary gland development needs to be elucidated. Previously, similar mammary gland defects from Rankl-deficient mice have been reported in mice lacking Id2. However, the downstream signaling pathway by which Rank signaling leads to mammary gland development is controversial. In this study, I showed that Rankl triggers marked nuclear localization of Id2 in mammary epithelial cells (MECs), and the defective nuclear translocation of Id2, but the normal expression of Cyclin D1, in the mammary epithelial cells of Rankl-/- mice. Moreover, I verified that Rankl stimulation induced phosphorylation of Id2 at serine 5, which led to nuclear retention of Id2. In the lactating Id2Tg

Rankl-/- mice, Id2 was not phosphorylated and was localized in the cytoplasm. In addition, in lactating Id2S5ATg mice, Id2S5A (serine 5 to alanine) was exclusively localized in the cytoplasm of MECs, while endogenous Id2 was localized in the nucleus. Intriguingly, nuclear expression of Id2S5A not only rescued increased apoptosis and defective differentiation of MECs in Rankl-/- mice, but also induced lactogenic differentiation of MECs in virgin wild-type mice. These results demonstrate that nuclear retention of Id2 due to Rank signaling plays a decisive role in survival and differentiation of MECs during mammary gland development.