HER2/ErbB2 Receptor Signaling in Rat and Human Prolactinoma Cells: Strategy for Targeted Prolactinoma Therapy
HER2/ErbB2 Receptor Signaling in Rat and Human Prolactinoma Cells: Strategy for Targeted Prolactinoma Therapy
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DOI：
10.1210/me.2010-0353
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Melmed, Shlomo
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文献类型：
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作者：
Fukuoka, Hidenori;Cooper, Odelia;Melmed, Shlomo
大约20%的泌乳素瘤患者会遇到多巴胺激动剂抵抗或不耐受。由于人表皮生长因子受体2（HER 2）/ErbB 2在泌乳素瘤中过表达，而ErbB受体配体调节泌乳素（PRL）基因表达，因此我们检测了HER 2/ErbB 2在泌乳素瘤激素调节和腺瘤细胞增殖中的作用，以评估靶向该受体用于泌乳素瘤治疗的基本原理。当我们显示泌乳素瘤HER 2过表达时，我们产生了组成型活性HER 2稳定的GH 3细胞转染子（HER 2CA）。在HER 2CA细胞中，PRL mRNA水平诱导约250倍，PRL分泌增强100倍，这也表现出增殖增加。拉帕替尼是一种表皮生长因子受体（EGFR）/ErbB 1和HER 2的双重酪氨酸激酶抑制剂（TKI），与EGFR/ErbB 1的TKI吉非替尼相比，拉帕替尼阻断受体信号传导，抑制PRL表达。拉帕替尼还抑制软琼脂中的菌落形成超过吉非替尼。口服拉帕替尼治疗导致HER 2CA转染接种的Wistar-Furth大鼠和雌激素诱导的Fi-scher 344大鼠泌乳素瘤的肿瘤缩小和血清PRL抑制。在来自切除的泌乳素瘤组织的培养人细胞中，拉帕替尼抑制PRL mRNA表达和分泌。这些结果表明，催乳素瘤HER 2有效地诱导PRL和调节实验性催乳素瘤细胞增殖。由于垂体HER 2信号传导被TKI消除，因此该受体可能是泌乳素瘤治疗的有效靶点。（分子内分泌学25：92-103，2011）
Dopamine agonist resistance or intolerance is encountered in approximately 20% of prolactinoma patients. Because human epidermal growth factor receptor 2 (HER2)/ErbB2 is overexpressed in pro-lactinomas and ErbB receptor ligands regulate prolactin (PRL) gene expression, we tested the role of HER2/ErbB2 in prolactinoma hormone regulation and adenoma cell proliferation to assess the rationale for targeting this receptor for prolactinoma therapy. As we showed prolactinoma HER2 overexpression, we generated constitutively active HER2-stable GH3 cell transfectants (HER2CA). PRL mRNA levels were induced approximately 250-fold and PRL secretion was enhanced 100-fold in HER2CA cells, which also exhibited increased proliferation. Lapatinib, a dual tyrosine kinase inhibitor (TKI) of both epidermal growth factor receptor (EGFR)/ErbB1 and HER2, blocked receptor signaling, and suppressed PRL expression more than gefitinib, a TKI of EGFR/ErbB1. Lapatinib also suppressed colony formation in soft agar more than gefitinib. Oral lapatinib treatment caused tumor shrinkage and serum PRL suppression both in HER2CA transfectant-inoculated Wistar-Furth rats and in estrogen-induced Fi-scher344 rat prolactinomas. In cultured human cells derived from resected prolactinoma tissue, lapatinib suppressed both PRL mRNA expression and secretion. These results demonstrate that prolactinoma HER2 potently induces PRL and regulates experimental prolactinoma cell proliferation. Because pituitary HER2 signaling is abrogated by TKIs, this receptor could be an effective target for prolactinoma therapy. (Molecular Endocrinology 25: 92-103, 2011)