Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones
Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones
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DOI：
10.1677/erc.1.01221
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发表时间：
2006-09-01
影响因子：
3.9
通讯作者：
Hyder, Salman M.
中科院分区：
文献类型：
--
作者：
Liang, Yayun;Brekken, Rolf A.;Hyder, Salman M.
血管内皮生长因子（VEGF）水平升高与乳腺癌抗激素治疗反应不佳有关。尽管VEGF被认为是一种内皮特异性生长因子，但最近的报告表明VEGF可以促进其他细胞类型的增殖，包括乳腺肿瘤细胞。我们描述了 VEGF 在乳腺癌细胞系中的增殖作用，这些作用通常用于了解雌激素、孕激素和抗激素对肿瘤生长的作用。由于类固醇激素可以增加某些乳腺癌细胞中的 VEGF 水平，因此我们评估了外源性 VEGF 对人乳腺癌细胞中抗雌激素 (ICI 182,780) 和 RU-486（抗孕激素米非司酮）生长抑制作用的影响。 VEGF(165) 和 VEGF(121) 通过细胞外信号调节激酶/丝裂原激活蛋白激酶 (ERK/MAPK) 途径增加表达 VEGFR-2（VEGF 受体 2）（flk/kdr）的肿瘤细胞系的增殖。此外，VEGF 诱导抗凋亡蛋白 Bcl-2 的表达，并通过 ICI 182,780 阻断 Bcl-2 的下调，甚至在 RU-486 存在的情况下，在 BT-474 和 T47-D 细胞中诱导 Bcl-2。即使在存在抗激素的情况下，VEGF 导致的 Bcl-2 水平升高也与肿瘤细胞的增殖和存活增加相关。这些结果表明，VEGF 刺激 VEGFR2 阳性肿瘤细胞的增殖，通过 Bcl-2 的表达和活性促进存活，并克服抗激素的生长抑制作用。这代表了临床样本中抗激素抵抗和肿瘤进展的潜在解释。因此，使用涉及抗激素和抗血管生成剂的联合治疗方式来治疗表达升高水平的 VEGF 的乳腺癌可能是有用的。
Increased levels of vascular endothelial growth factor (VEGF) are associated with a poor response of breast cancer to anti-hormone treatment. Although VEGF is regarded as an endothelial-specific growth factor, recent reports have shown that VEGF can promote proliferation of other cell types, including breast tumor cells. We have characterized the proliferative effects of VEGF in breast cancer cell lines that are commonly used for understanding the role of estrogens, progestins, and anti-hormones on tumor growth. Since steroid hormones can increase the level of VEGF in certain breast cancer cells, we evaluated the effects of exogenous VEGF on the growth-suppressive effects of anti-estrogen (ICI 182,780) and RU-486 (anti-progestin mifepristone) in human breast cancer cells. VEGF(165) and VEGF(121) increased the proliferation of tumor cell lines that expressed VEGFR-2 (VEGF receptor 2) (flk/kdr) via the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway. Furthermore, VEGF induced the expression of the anti-apoptotic protein Bcl-2 and blocked down-regulation of Bcl-2 by ICI 182,780 and induced Bcl-2 in BT-474 and T47-D cells even in the presence of RU-486. Increased Bcl-2 levels in response to VEGF were associated with increased proliferation and survival of tumor cells even in the presence of anti-hormones. These results suggest that VEGF stimulates proliferation of VEGFR2-positive tumor cells, promotes survival via the expression and activity of Bcl-2 and overrides the growth-suppressive effects of anti-hormones. This represents a potential explanation for anti-hormone resistance and tumor progression in clinical samples. Thus, it may be useful to use combined modality treatment involving anti-hormones and anti-angiogenic agents to treat breast cancers that express elevated levels of VEGF.