Reduced annexin A6 expression promotes the degradation of activated epidermal growth factor receptor and sensitizes invasive breast cancer cells to EGFR-targeted tyrosine kinase inhibitors.
Reduced annexin A6 expression promotes the degradation of activated epidermal growth factor receptor and sensitizes invasive breast cancer cells to EGFR-targeted tyrosine kinase inhibitors.
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DOI：
10.1186/1476-4598-12-167
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发表时间：
2013-12-19
期刊：
影响因子：
37.3
通讯作者：
Sakwe AM
中科院分区：
文献类型：
--
作者：
Koumangoye RB;Nangami GN;Thompson PD;Agboto VK;Ochieng J;Sakwe AM
膜联蛋白A6（AnxA 6）在AnxA 6缺陷型非侵袭性肿瘤细胞中的表达已显示终止表皮生长因子受体（EGFR）活化和下游信号传导。然而，作为支架蛋白，AnxA 6可以稳定活化的细胞表面受体，以促进细胞过程，如肿瘤细胞的运动性和侵袭性。在这项研究中，我们研究了AnxA 6在浸润性乳腺癌细胞中EGFR活性的贡献，并检查了AnxA 6的表达状态是否影响这些细胞对EGFR靶向酪氨酸激酶抑制剂（TKI）的反应和/或患者生存率。我们证明，在侵袭性BT-549乳腺癌细胞中，AnxA 6表达是激活的（phosho-Y1068）EGFR持续膜定位所必需的，因此，MAP激酶ERK 1/2和磷酸肌醇3-激酶/Akt通路的持续激活。这些细胞中AnxA 6的耗竭伴随着活化的EGFR的快速降解，减弱的下游信号传导和预期的增强的锚定非依赖性生长。除了抑制细胞运动性和侵袭性外，AnxA 6缺失的细胞对EGFR靶向TKI拉帕替尼和PD 153035也更敏感。我们还提供了证据表明，AnxA 6表达减少与基底细胞样乳腺癌患者更好的无复发生存率相关，但无远处转移和总生存率较差。总之，这表明AnxA 6耗尽的侵袭性肿瘤细胞中活化EGFR的快速降解是其对EGFR靶向TKI的敏感性和运动性降低的基础。这些数据还表明，AnxA 6表达状态可能有助于预测基底细胞样乳腺癌患者对EGFR靶向治疗有反应的生存率和可能性。
The expression of annexin A6 (AnxA6) in AnxA6-deficient non-invasive tumor cells has been shown to terminate epidermal growth factor receptor (EGFR) activation and downstream signaling. However, as a scaffolding protein, AnxA6 may stabilize activated cell-surface receptors to promote cellular processes such as tumor cell motility and invasiveness. In this study, we investigated the contribution of AnxA6 in the activity of EGFR in invasive breast cancer cells and examined whether the expression status of AnxA6 influences the response of these cells to EGFR-targeted tyrosine kinase inhibitors (TKIs) and/or patient survival. We demonstrate that in invasive BT-549 breast cancer cells AnxA6 expression is required for sustained membrane localization of activated (phosho-Y1068) EGFR and consequently, persistent activation of MAP kinase ERK1/2 and phosphoinositide 3-kinase/Akt pathways. Depletion of AnxA6 in these cells was accompanied by rapid degradation of activated EGFR, attenuated downstream signaling and as expected enhanced anchorage-independent growth. Besides inhibition of cell motility and invasiveness, AnxA6-depleted cells were also more sensitive to the EGFR-targeted TKIs lapatinib and PD153035. We also provide evidence suggesting that reduced AnxA6 expression is associated with a better relapse-free survival but poorer distant metastasis-free and overall survival of basal-like breast cancer patients. Together this demonstrates that the rapid degradation of activated EGFR in AnxA6-depleted invasive tumor cells underlies their sensitivity to EGFR-targeted TKIs and reduced motility. These data also suggest that AnxA6 expression status may be useful for the prediction of the survival and likelihood of basal-like breast cancer patients to respond to EGFR-targeted therapies.
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