Wang Ying-Xue, Gao Jin-Xiang, Wang Xiu-Yun, Zhang Li, Liu Chang-Mei
Department of Endocrinology, School of Clinical Medicine, Binzhou Medical University, No.661, Yellow-River Second Street, 256603 Binzhou, China.
Tumour Biol. 2012 Aug;33(4):957-66. doi: 10.1007/s13277-012-0324-4. Epub 2012 Jan 18.
Breast cancer is the most common malignancy in women, and many breast cancer patients fail conventional treatment strategies of chemotherapy, radiation, and antiestrogen therapy. Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor (ER) pathway. Combination of EGFR and COX-2 inhibitors, therefore, could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer. In order to verify the effects of EGFR and COX-2 inhibitors, breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors (nimotuzumab and celecoxib) alone and in combination. Both cell lines were sensitive to celecoxib, but not to nimotuzumab. However, combination of two drugs demonstrated synergistic effects on cell killing. Moreover, association of two drugs resulted in SKBR-3 cells, a further G0/G1 phase arrest than one drug alone. Downregulation of p-EGFR, p-Akt, p-mTOR, and amplified in breast cancer 1 (AIB1) were observed in both cell lines, and upregulation of E-cadherin was only found in MCF-7, after treatment with single agent or in combination. These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer, which partly correlates with ER status. Due to Akt/mTOR, EMT and AIB1 pathways participate in this process, therefore, E-cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors.
乳腺癌是女性中最常见的恶性肿瘤，许多乳腺癌患者对化疗、放疗和抗雌激素治疗等传统治疗策略无效。对参与乳腺癌发展的分子途径和生物标志物的研究应能产生指导治疗决策的信息。表皮生长因子受体（EGFR）和环氧合酶-2（COX-2）参与乳腺癌的致癌过程，并与雌激素受体（ER）途径存在紧密的相互作用。因此，EGFR和COX-2抑制剂联合使用可能是减少雌激素依赖性乳腺癌细胞生长的有效策略。为了验证EGFR和COX-2抑制剂的作用，对乳腺癌细胞MCF-7和SKBR-3进行了受体状态表征，然后分别单独及联合使用各自的抑制剂（尼妥珠单抗和塞来昔布）进行处理。两种细胞系对塞来昔布敏感，但对尼妥珠单抗不敏感。然而，两种药物联合使用对细胞杀伤显示出协同作用。此外，两种药物联合使用导致SKBR-3细胞比单独使用一种药物时进一步停滞在G0/G1期。在两种细胞系中均观察到p-EGFR、p-Akt、p-mTOR和乳腺癌扩增1（AIB1）的下调，而在用单药或联合用药处理后，E-钙黏蛋白的上调仅在MCF-7中发现。这些研究表明，尼妥珠单抗和塞来昔布在乳腺癌中发挥协同抗增殖作用，这部分与ER状态相关。由于Akt/mTOR、上皮-间质转化（EMT）和AIB1途径参与了这一过程，因此，E-钙黏蛋白和AIB1可被视为预测EGFR和COX-2抑制剂治疗ER阳性乳腺癌细胞反应的可能生物标志物。
