Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) Promotes Growth and Survival of Breast Epithelial Cells: Novel Regulation of the Estrogen Receptor
Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) Promotes Growth and Survival of Breast Epithelial Cells: Novel Regulation of the Estrogen Receptor
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DOI：
10.1210/en.2012-1970
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发表时间：
2013-05-01
期刊：
影响因子：
4.8
通讯作者：
Holly, Jeff M. P.
中科院分区：
文献类型：
--
作者：
Foulstone, Emily J.;Zeng, Li;Holly, Jeff M. P.
在乳腺肿瘤中，IGF结合蛋白-2（IGFBP-2）升高，IGFBP-2的存在已被证明与恶性肿瘤相关。然而，IGFBP-2如何促进恶性状态仍不清楚。沉默IGFBP-2阻断细胞增殖，并在MCF-7细胞中增加细胞死亡，表明IGFBP-2在促有丝分裂和存活能力中起作用。外源性IGFBP-2通过整联蛋白受体降低磷酸酶和张力蛋白同源物10号染色体缺失（PTEN）水平，保护这些细胞免受各种化疗药物诱导的死亡。这依赖于功能性雌激素受体（ER）-α，因为沉默ER-α阻断了IGFBP-2赋予细胞存活的能力。IGFBP-2的缺失增加了PTEN的水平，提高了细胞的化学敏感性，证实了其作为生存因子的作用。沉默IGFBP-2对IGF-II的反应没有影响，但由于ER-α的丢失，不再观察到对雌激素和他莫昔芬的反应，这可以通过抑制PTEN来预防。相反，外源性IGFBP-2通过与整合素受体的相互作用增加正常细胞和癌细胞中ER-α mRNA和蛋白质。IGFBP-2对ER-α的这些作用涉及癌细胞中的IGF-I受体和磷脂酰肌醇3-激酶的激活，但在正常乳腺细胞中与此无关。乳腺癌细胞产生IGFBP-2可增强其增殖潜力，增加其存活率，并保护其免受化疗诱导的死亡。IGFBP-2不仅调节IGFs和直接调节PTEN，而且在维持ER-α表达中起作用。（内分泌学154：1780-1793，2013）
In breast tumors IGF binding protein-2 (IGFBP-2) is elevated, and the presence of IGFBP-2 has been shown to correlate with malignancy. However, how IGFBP-2 contributes to the malignant state is still unclear. Silencing IGFBP-2 blocked cell proliferation and in MCF-7 cells increased cell death, indicating that IGFBP-2 was acting in both a mitogenic and a survival capacity. Exogenous IGFBP-2 acting via integrin receptors to reduce phosphatase and tensin homolog deleted from chromosome 10 (PTEN) levels protected these cells against death induced by various chemotherapeutic agents. This was dependent on a functional estrogen receptor (ER)-alpha because silencing ER-alpha blocked the ability of IGFBP-2 to confer cell survival. Loss of IGFBP-2 increased levels of PTEN and improved chemosensitivity of the cells, confirming its role as a survival factor. Silencing IGFBP-2 had no effect on the response to IGF-II, but responses to estrogen and tamoxifen were no longer observed due to loss of ER-alpha, which could be prevented by the inhibition of PTEN. Conversely, exogenous IGFBP-2 increased ER-alpha mRNA and protein in both normal and cancer cells via its interaction with integrin receptors. These actions of IGFBP-2 on ER-alpha involved the IGF-I receptor and activation of phosphatidylinositol 3-kinase in the cancer cells but were independent of this in normal breast cells. The production of IGFBP-2 by breast cancer cells enhances their proliferative potential, increases their survival, and protects them against chemotherapy-induced death. IGFBP-2 not only modulates IGFs and directly regulates PTEN but also has a role in maintaining ER-alpha expression. (Endocrinology 154: 1780-1793, 2013)