Inflammatory breast cancer (IBC) is an uncommon and highly aggressive form of breast cancer. The disease is characterized by rapid progression with approximately 50% of IBC patients to have human epidermal growth factor receptor 2 (HER2) amplification. HER2-positive IBC is associated with unfavourable prognosis and increased risk of brain metastasis. Ironically, HER2-positive metastatic breast cancer is still prevalent where therapeutic targeting of HER2-receptor is well developed. In addition, the ability to accurately predict the risk of metastatic potential in these cells poses a substantial challenge. Lapatinib (Lap), a dual kinase inhibitor of HER2 and epidermal growth factor receptor is used in the treatment of advanced HER-2 positive breast cancers and is currently being evaluated in the adjuvant setting. In this study, we report the effectiveness of Lap in the suppression of low-dose response to doxorubicin (Dox) in HER2-positive SKBR3 cells. Upon treatment of SKBR3 cells with 0.1 µM of Dox, the cell viability was significantly increased as compared to the human mammary fibroblasts, and triple-negative human breast cancer MDA-MB-231 cells. Interestingly, the effect of 0.1 µM Dox revealed morphological changes consistent with a significant increase in the formation of prominent F-actin filaments and mitochondrial spread compared with the control SKBR3 cells. Furthermore, an enhanced migration was also evident in these cells. However, a combinational dose of 0.1 µM Dox + 5 µM Lap suppressed the observed phenotypic changes in the 0.1 µM Dox treated SKBR3 cells. There was a significant difference in the prominent F-actin filaments and the mitochondrial spread compared with the 0.1 µM Dox versus combination regimen of 0.1 µM Dox + 5 µM Lap. In addition, the combinational therapy showed a decrease in the percentage of wound closure when compared to the control. Hence, the combinational therapy in which Lap suppresses the low-dose effect of Dox in SKBR3 cells may provide an effective intervention strategy for reducing the risk of metastasis in HER2-positive breast cancers.

中文翻译：

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拉帕替尼抑制阿霉素诱导的HER2阳性乳腺癌细胞迁移。

炎性乳腺癌（IBC）是一种罕见且高度侵袭性的乳腺癌。该疾病的特征是快速发展，大约50％的IBC患者具有人类表皮生长因子受体2（HER2）扩增。HER2阳性的IBC与预后不良和脑转移风险增加有关。具有讽刺意味的是，HER2阳性转移性乳腺癌仍很普遍，这是针对HER2受体的治疗靶点。此外，准确预测这些细胞中转移潜能风险的能力提出了重大挑战。拉帕替尼（Lap）是HER2和表皮生长因子受体的双重激酶抑制剂，用于治疗晚期HER-2阳性乳腺癌，目前正在辅助治疗中进行评估。在这个研究中，我们报道了Lap在抑制HER2阳性SKBR3细胞中对阿霉素（Dox）的低剂量应答中的有效性。用0.1 µM Dox处理SKBR3细胞后，与人乳腺成纤维细胞和三阴性人类乳腺癌MDA-MB-231细胞相比，细胞活力显着提高。有趣的是，与对照SKBR3细胞相比，0.1 µM Dox的影响揭示了形态上的变化，与显着F-肌动蛋白丝的形成和线粒体扩散的显着增加一致。此外，在这些细胞中迁移的增强也很明显。但是，0.1 µM Dox + 5 µM Lap的联合剂量抑制了在0.1 µM Dox处理的SKBR3细胞中观察到的表型变化。与0.1 µM Dox和0.1 µM Dox + 5 µM Lap的联合治疗方案相比，显着的F-肌动蛋白丝和线粒体分布差异显着。另外，与对照相比，联合疗法显示伤口闭合百分比降低。因此，Lap抑制SKBR3细胞中Dox的低剂量作用的联合疗法可为降低HER2阳性乳腺癌转移风险提供有效的干预策略。