Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin pathway: Progesterone receptor as a potential indicator of growth factor activity in breast cancer
Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin pathway: Progesterone receptor as a potential indicator of growth factor activity in breast cancer
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DOI：
10.1210/me.2002-0318
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发表时间：
2003-04-01
影响因子：
--
通讯作者：
Lee, AV
中科院分区：
文献类型：
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作者：
Cui, XJ;Zhang, P;Lee, AV
虽然雌激素和生长因子信号通路之间的相互作用已被广泛研究，但生长因子和孕酮如何相互调节尚不清楚。在这项研究中，我们发现IGF-I显著降低乳腺癌细胞中孕激素受体（PR）mRNA和蛋白水平。其他生长因子，如表皮生长因子，也表现出同样的效果。PR水平的降低与PR活性降低相关。与孕激素不同，IGF-I不利用蛋白酶体下调PR。相反，IGF-1介导的PR水平降低是通过抑制PR基因转录实现的。此外，磷脂酰肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路被发现特异性参与IGF-I的这种作用。我们的数据还表明，IGF-I下调PR不是通过降低雌激素受体（ER）水平或活性介导的。首先，IGF-I诱导配体非依赖性ER活性，同时降低ER依赖性PR水平。其次，PR和细胞周期蛋白D1都是ER上调的，IGF-I增加细胞周期蛋白D1水平，同时降低PR水平。第三，组成性激活PI 3 K或Akt诱导ER活性，但降低PR水平和活性。综上所述，我们的数据表明IGF-I通过PI 3 K/Akt/mTOR通路抑制乳腺癌细胞中的PR表达。由于原发性乳腺癌中PR低或缺失与预后不良和对激素治疗的反应相关，我们的研究结果表明，PR低状态可作为乳腺肿瘤细胞中活化生长因子信号传导的指标，因此是侵袭性肿瘤表型和对激素治疗耐药的指标。
Although interactions between estrogen and growth factor signaling pathways have been studied extensively, how growth factors and progesterone regulate each other is less clear. In this study, we found that IGF-I sharply lowers progesterone receptor (PR) mRNA and protein levels in breast cancer cells. Other growth factors, such as epidermal growth factor, also showed the same effect. The decrease of PR levels was associated with reduced PR activity. Unlike progestins, IGF-I does not utilize the proteasome for down-regulating PR. Instead, the IGF-1-mediated decrease in PR levels is via an inhibition of PR gene transcription. In addition, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was found to be specifically involved in this IGF-I effect. Our data also suggest that the IGF-I down-regulation of PR is not mediated via a reduction of estrogen receptor (ER) levels or activity. First, IGF-I induced ligand-independent ER activity while reducing ER-dependent PR levels. Second, whereas PR and cyclin D1 are both ER up-regulated, IGF-I increased cyclin D1 levels while decreasing PR levels. Third, constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity. Taken together, our data indicate that IGF-I inhibits PR expression in breast cancer cells via the PI3K/Akt/mTOR pathway. Because low or absent PR in primary breast cancer is associated with poor prognosis and response to hormone therapy, our results suggest that low PR status may serve as an indicator of activated growth factor signaling in breast tumor cells, and therefore of an aggressive tumor phenotype and resistance against hormonal therapy.