Saxena Neeraj K, Taliaferro-Smith LaTonia, Knight Brandi B, Merlin Didier, Anania Frank A, O'Regan Ruth M, Sharma Dipali
Department of Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Cancer Res. 2008 Dec 1;68(23):9712-22. doi: 10.1158/0008-5472.CAN-08-1952.
Obesity is an independent risk factor for breast cancer, and obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Obesity, as associated with metabolic syndrome, results in an increase in circulating insulin-like growth factor (IGF), which acts as a mitogen. In addition, higher plasma level of adipocytokine leptin is associated with obesity. In the present study, we show that cotreatment with leptin and IGF-I significantly increases proliferation as well as invasion and migration of breast cancer cells. We found a novel bidirectional crosstalk between leptin and IGF-I signaling; IGF-I induced phosphorylation of leptin receptor (Ob-Rb) and leptin induced phosphorylation of IGF-I receptor (IGF-IR), whereas cotreatment induced synergistic phosphorylation and association of Ob-Rb and IGF-IR along with activation of downstream effectors, Akt and extracellular signal-regulated kinase. Leptin increased phosphorylation of IGF signaling molecules insulin-receptor substrate (IRS)-1 and IRS-2. Interestingly, we found that leptin and IGF-I cotreatment synergistically transactivated epidermal growth factor receptor (EGFR), depending on the proteolytic release of EGFR ligands, as the broad-spectrum matrix metalloproteinase inhibitor GM6001 could inhibit this effect. Using clinically relevant EGFR inhibitors, erlotinib and lapatinib, we found that inhibition of EGFR activation effectively inhibited leptin- and IGF-I-induced invasion and migration of breast cancer cells. Taken together, these data suggest a novel bidirectional crosstalk between leptin and IGF-I signaling that transactivates EGFR and promotes the metastatic properties as well as invasion and migration of breast cancer cells. Our findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the procancerous effects of leptin and IGF-I in breast cancers.
肥胖是乳腺癌的独立危险因素，肥胖的乳腺癌患者出现更大肿瘤负荷和转移增加的风险更高。肥胖与代谢综合征相关，会导致循环胰岛素样生长因子（IGF）增加，该因子起有丝分裂原的作用。此外，较高的血浆脂肪细胞因子瘦素水平与肥胖相关。在本研究中，我们表明瘦素与IGF-I联合处理可显著增加乳腺癌细胞的增殖以及侵袭和迁移。我们发现瘦素与IGF-I信号传导之间存在一种新型双向串扰；IGF-I诱导瘦素受体（Ob-Rb）磷酸化，瘦素诱导IGF-I受体（IGF-IR）磷酸化，而联合处理诱导Ob-Rb和IGF-IR的协同磷酸化和结合以及下游效应物Akt和细胞外信号调节激酶的激活。瘦素增加IGF信号分子胰岛素受体底物（IRS）-1和IRS-2的磷酸化。有趣的是，我们发现瘦素与IGF-I联合处理协同反式激活表皮生长因子受体（EGFR），这取决于EGFR配体的蛋白水解释放，因为广谱基质金属蛋白酶抑制剂GM6001可抑制这种效应。使用临床相关的EGFR抑制剂厄洛替尼和拉帕替尼，我们发现抑制EGFR激活可有效抑制瘦素和IGF-I诱导的乳腺癌细胞侵袭和迁移。综上所述，这些数据表明瘦素与IGF-I信号传导之间存在一种新型双向串扰，可反式激活EGFR并促进乳腺癌细胞的转移特性以及侵袭和迁移。我们的研究结果表明使用EGFR抑制剂厄洛替尼和拉帕替尼来对抗瘦素和IGF-I在乳腺癌中的促癌作用的可能性。
