National Center for Cell Science (NCCS), NCCS Complex, Pune 411 007, India.
Mol Cancer. 2010 May 7;9:101. doi: 10.1186/1476-4598-9-101.
Breast cancer is one of the most frequently diagnosed cancer and accounts for over 400,000 deaths each year worldwide. It causes premature death in women, despite progress in early detection, treatment, and advances in understanding the molecular basis of the disease. Therefore, it is important to understand the in depth mechanism of tumor progression and develop new strategies for the treatment of breast cancer. Thus, this study is aimed at gaining an insight into the molecular mechanism by which osteopontin (OPN), a member of SIBLING (Small Integrin Binding LIgand N-linked Glycoprotein) family of protein regulates tumor progression through activation of various transcription factors and expression of their downstream effector gene(s) in breast cancer.
In this study, we report that purified native OPN induces ICAM-1 expression in breast cancer cells. The data revealed that OPN induces NF-kappaB activation and NF-kappaB dependent ICAM-1 expression. We also observed that OPN-induced NF-kappaB further controls AP-1 transactivation, suggesting that there is cross talk between NF-kappaB and AP-1 which is unidirectional towards AP-1 that in turn regulates ICAM-1 expression in these cells. We also delineated the role of mTOR and p70S6 kinase in OPN-induced ICAM-1 expression. The study suggests that inhibition of mTOR by rapamycin augments whereas overexpression of mTOR/p70S6 kinase inhibits OPN-induced ICAM-1 expression. Moreover, overexpression of mTOR inhibits OPN-induced NF-kappaB and AP-1-DNA binding and transcriptional activity. However, rapamycin further enhanced these OPN-induced effects. We also report that OPN induces p70S6 kinase phosphorylation at Thr-421/Ser-424, but not at Thr-389 or Ser-371 and mTOR phosphorylation at Ser-2448. Overexpression of mTOR has no effect in regulation of OPN-induced phosphorylation of p70S6 kinase at Thr-421/Ser-424. Inhibition of mTOR by rapamycin attenuates Ser-371 phosphorylation but does not have any effect on Thr-389 and Thr-421/Ser-424 phosphorylation of p70S6 kinase. However, OPN-induced phosphorylation of p70S6 kinase at Thr-421/Ser-424 is being controlled by MEK/ERK pathway.
These results suggest that blocking of OPN-induced ICAM-1 expression through mTOR/p70S6 kinase signaling pathway may be an important therapeutic strategy for the treatment of breast cancer.
乳腺癌是最常见的癌症之一，全球每年有超过 40 万人因此死亡。尽管在早期检测、治疗和对疾病分子基础的理解方面取得了进展，但它仍导致女性早逝。因此，了解肿瘤进展的深入机制并开发治疗乳腺癌的新策略非常重要。因此，本研究旨在深入了解骨桥蛋白（OPN）作为 SIBLING（Small Integrin Binding LIgand N-linked Glycoprotein）家族蛋白的一员，通过激活各种转录因子并表达其下游效应基因来调节乳腺癌中肿瘤进展的分子机制。
在这项研究中，我们报告说，纯化的天然 OPN 可诱导乳腺癌细胞中 ICAM-1 的表达。数据显示，OPN 诱导 NF-κB 激活和 NF-κB 依赖性 ICAM-1 表达。我们还观察到 OPN 诱导的 NF-κB 进一步控制 AP-1 反式激活，表明 NF-κB 和 AP-1 之间存在单向交叉对话，这反过来又调节这些细胞中 ICAM-1 的表达。我们还阐明了 mTOR 和 p70S6 激酶在 OPN 诱导的 ICAM-1 表达中的作用。该研究表明，雷帕霉素抑制 mTOR 会增强，而过表达 mTOR/p70S6 激酶会抑制 OPN 诱导的 ICAM-1 表达。此外，过表达 mTOR 会抑制 OPN 诱导的 NF-κB 和 AP-1-DNA 结合和转录活性。然而，雷帕霉素进一步增强了这些 OPN 诱导的作用。我们还报告说，OPN 诱导 p70S6 激酶在 Thr-421/Ser-424 处磷酸化，但不磷酸化 Thr-389 或 Ser-371，mTOR 在 Ser-2448 处磷酸化。过表达 mTOR 对 OPN 诱导的 p70S6 激酶在 Thr-421/Ser-424 处的磷酸化没有影响。雷帕霉素抑制 mTOR 会减弱 Ser-371 磷酸化，但对 Thr-389 和 Thr-421/Ser-424 处的 p70S6 激酶磷酸化没有影响。然而，OPN 诱导的 p70S6 激酶在 Thr-421/Ser-424 处的磷酸化受 MEK/ERK 通路控制。
这些结果表明，通过 mTOR/p70S6 激酶信号通路阻断 OPN 诱导的 ICAM-1 表达可能是治疗乳腺癌的重要治疗策略。
