Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland
Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland
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DOI：
10.1073/pnas.0915148107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Brisken, Cathrin
中科院分区：
文献类型：
--
作者：
Beleut, Manfred;Rajaram, Renuga Devi;Brisken, Cathrin
在雌性生殖激素的控制下，小鼠的乳腺在出生后发育。雌激素和孕激素通过作用于表达其同源受体雌激素受体α(ERα)和孕激素受体(PR)的乳腺上皮细胞(MECs)的亚群，通过鲜为人知的机制来触发形态发生。在这里，我们展示了在成年女性中，孕酮分两波驱动微血管内皮细胞的增殖。第一个小波，包括PR(+)细胞，需要细胞周期蛋白D1；第二个大波，主要由PR(-)细胞组成，依赖于肿瘤坏死因子(TNF)家族成员，即核因子-kappa B配体(RANKL)的受体激活因子。RANKL通过旁分泌机制诱导细胞增殖。去除乳腺上皮中的RANKL可阻断孕酮诱导的形态发生，而RANKL在微血管内皮细胞中的异位表达可完全挽救PR-/-表型。在没有PR信号的情况下，全身应用RANKL可触发细胞增殖，注射RANK信号抑制剂可干扰孕酮诱导的细胞增殖。因此，孕酮通过一种细胞固有的、更重要的旁分泌机制来促进细胞增殖。
The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor alpha (ER alpha) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-kappa B-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR-/- phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.