Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers.
Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers.
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DOI：
10.1007/s12672-010-0048-0
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发表时间：
2010-10
影响因子：
3
通讯作者：
Haslam SZ
中科院分区：
文献类型：
--
作者：
Kariagina A;Xie J;Leipprandt JR;Haslam SZ
雌激素 (E) 和孕激素 (P) 都与人类乳腺癌的病因有关。定义它们的作用机制，特别是在体内，与乳腺癌的预防和治疗相关。我们研究了正常大鼠乳腺和激素依赖性大鼠乳腺癌中 E 和/或 P 诱导的体内增殖的分子和细胞机制，这些乳腺癌与正常人类乳腺癌和激素依赖性乳腺癌具有许多共同特征。我们发现，与单独使用 E 相比，E+P 治疗可显着诱导正常腺癌和乳腺癌的增殖。在正常腺体和肿瘤中，E+P 诱导的增殖是通过增加双调蛋白 (Areg)（一种表皮生长因子受体 (EGFR) 配体）的产生以及激活 EGFR 下游调节增殖的细胞内信号通路（Erk、Akt、JNK）来介导的。使用大鼠原代乳腺类器官或 T47D 乳腺癌细胞的体外实验证实，Areg 和合成孕激素 R5020 可通过 EGFR 信号传导协同促进细胞增殖。易瑞沙（Iressa）是一种 EGFR 抑制剂，可有效阻止这种增殖。这些结果表明，E、P 和 EGFR 通路之间的串扰介质可被视为治疗激素依赖性乳腺癌的相关分子靶点，尤其是绝经前女性。本文的在线版本 (doi:10.1007/s12672-010-0048-0) 包含补充材料，可供授权用户使用。
Both estrogen (E) and progesterone (P) are implicated in the etiology of human breast cancer. Defining their mechanisms of action, particularly in vivo, is relevant to the prevention and therapy of breast cancer. We investigated the molecular and cellular mechanisms of E and/or P-induced in vivo proliferation, in the normal rat mammary gland and in hormone-dependent rat mammary cancers which share many characteristics with the normal human breast and hormone-dependent breast cancers. We show that E+P treatment induced significantly greater proliferation in both the normal gland and mammary cancers compared to E alone. In both the normal gland and tumors, E+P-induced proliferation was mediated through the increased production of amphiregulin (Areg), an epidermal growth factor receptor (EGFR) ligand, and the activation of intracellular signaling pathways (Erk, Akt, JNK) downstream of EGFR that regulate proliferation. In vitro experiments using rat primary mammary organoids or T47D breast cancer cells confirmed that Areg and the synthetic progestin, R5020, synergize to promote cell proliferation through EGFR signaling. Iressa, an EGFR inhibitor, effectively blocked this proliferation. These results indicate that mediators of cross talk between E, P, and EGFR pathways may be considered as relevant molecular targets for the therapy of hormone-dependent breast cancers, especially in premenopausal women. The online version of this article (doi:10.1007/s12672-010-0048-0) contains supplementary material, which is available to authorized users.