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缺乏雄激素受体的雌性小鼠和MCF7乳腺癌细胞中乳腺发育异常和生长迟缓。

Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.

作者信息

Yeh Shuyuan, Hu Yueh-Chiang, Wang Peng-Hui, Xie Chao, Xu Qingquan, Tsai Meng-Yin, Dong Zhihong, Wang Ruey-Sheng, Lee Ting-Hein, Chang Chawnshang

机构信息

Department of Pathology, University of Rochester, Rochester, NY 14642, USA.

出版信息

J Exp Med. 2003 Dec 15;198(12):1899-908. doi: 10.1084/jem.20031233.

DOI:10.1084/jem.20031233
PMID:14676301
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2194158/
Abstract

Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR-/-) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR-/- mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR-/- MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.

摘要

对缺乏雄激素受体（AR）的雌性小鼠（AR-/-）进行的表型分析表明，乳腺发育在青春期前阶段受到阻碍，导管分支减少，终末芽中的Cap细胞数量减少，成年雌性小鼠的小叶腺泡发育减少，哺乳期腺体中产生乳汁的肺泡数量减少。AR-/-乳腺的发育缺陷涉及胰岛素样生长因子I-胰岛素样生长因子I受体和丝裂原活化蛋白激酶（MAPK）信号以及雌激素受体（ER）活性的缺陷。在AR-/- MCF7乳腺癌细胞中也发现了类似的生长迟缓以及生长因子介导的Ras/Raf/MAPK级联和ER信号传导缺陷。恢复实验表明，AR的NH2末端/DNA结合结构域而非配体结合结构域对于MCF7细胞中的正常MAPK功能至关重要，并且在男性乳腺癌中发现的AR突变体（R608K）与MAPK的过度激活有关。总之，我们的数据提供了首个体内证据，表明AR介导的MAPK和ER激活可能在乳腺发育和MCF7乳腺癌细胞增殖中发挥重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/12cc31b5c651/20031233f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/68178f89e8ec/20031233f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/ac1132feabb8/20031233f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/3ae395412c75/20031233f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/9c8f7dcec302/20031233f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/6e2f52ef464d/20031233f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/12cc31b5c651/20031233f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/68178f89e8ec/20031233f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/ac1132feabb8/20031233f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/3ae395412c75/20031233f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/9c8f7dcec302/20031233f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/6e2f52ef464d/20031233f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/2194158/12cc31b5c651/20031233f6.jpg

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