Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1G protein-coupled receptor via repression of ERα, Akt1, and Stat5.
Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1G protein-coupled receptor via repression of ERα, Akt1, and Stat5.
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DOI：
10.1111/j.1600-079x.2012.01000.x
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发表时间：
2012-10
影响因子：
10.3
通讯作者：
Hill SM
中科院分区：
文献类型：
--
作者：
Xiang S;Mao L;Yuan L;Duplessis T;Jones F;Hoyle GW;Frasch T;Dauchy R;Blask DE;Chakravarty G;Hill SM
为了确定褪黑素是否通过其MT1 G蛋白偶联受体（GPCR）影响小鼠乳腺发育，我们培育了小鼠乳腺肿瘤病毒(MMTV)-MT1- flag -乳腺过表达（MT1- moe）转基因小鼠。MT1-mOE转基因雌性小鼠的乳腺中MT1-Flag基因的表达增加，并在妊娠和哺乳期进一步显著增加。MT1-mOE小鼠乳腺全载显示导管生长、导管分支和终末芽（TEB）形成显著减少。妊娠期和哺乳期雌性MT1- moe小鼠MT1受体表达升高与小叶肺泡发育减少、乳腺上皮细胞增殖抑制和哺乳幼崽体重显著降低有关。妊娠期和哺乳期MT1- moe小鼠MT1表达升高与乳腺中Akt1、phospho-Stat5、Wnt4、雌激素受体α (ERα)、孕激素受体（PR） A和B、乳蛋白β-酪蛋白和乳清酸性蛋白（WAP）表达降低相关。雌激素和孕激素刺激的乳腺发育受到MT1受体表达升高和外源性褪黑激素的抑制。这些研究表明，MT1褪黑素受体及其配体褪黑素通过抑制生长和改变发育模式在小鼠乳腺发育和泌乳中发挥重要的调节作用。
To determine if melatonin, via its MT1 G protein-coupled receptor (GPCR), impacts mouse mammary gland development, we generated a mouse mammary tumor virus (MMTV)-MT1-Flag-mammary gland over-expressing (MT1-mOE) transgenic mouse. Increased expression of the MT1-Flag transgene was observed in the mammary glands of pubescent MT1-mOE transgenic female mice, with further significant increases during pregnancy and lactation. Mammary gland whole mounts from MT1-mOE mice showed significant reductions in ductal growth, ductal branching, and terminal end bud (TEB) formation. Elevated MT1 receptor expression in pregnant and lactating female MT1-mOE mice was associated with reduced lobulo-alveolar development, inhibition of mammary epithelial cell proliferation, and significant reductions in body weights of suckling pups. Elevated MT1 expression in pregnant and lactating MT1-mOE mice correlated with reduced mammary gland expression of Akt1, phospho-Stat5, Wnt4, estrogen receptor alpha (ERα), progesterone receptors (PR) A and B, and milk proteins β-casein and whey acidic protein (WAP). Estrogen and progesterone stimulated mammary gland development was repressed by elevated MT1 receptor expression and exogenous melatonin administration. These studies demonstrate that the MT1 melatonin receptor and its ligand melatonin play an important regulatory role in mammary gland development and lactation in mice through both growth suppression and alteration of developmental paradigms.