Department of Nanotechnology and Advanced Materials, Advanced Technology Research and Application Center, Selcuk University, Konya, Turkey.
Meram Vocational School, Medicinal and Aromatic Plants Program, Necmettin Erbakan University, Konya, Turkey.
Clin Exp Med. 2021 Aug;21(3):447-456. doi: 10.1007/s10238-021-00685-0. Epub 2021 Jan 20.
Breast cancer (BC) is the leading cause of cancer deaths in women. One of the reasons for the failure of BC treatment is reportedly the ineffectiveness of chemotherapeutic drugs against breast cancer stem-like cells (BCSCs). HER2 receptors have an important role in the self-renewal of BCSCs. Matrix metalloproteinase (MMP) and cytokine levels were found to be higher in BCSCs, which demonstrates their potential metastatic capacity. Therefore, the aim of this study was to evaluate the response of BCSCs to trastuzumab and to investigate the MMP levels in primary breast cancer cells and HER2 BCSCs. Tumour tissue samples were obtained during surgical intervention from ten breast cancer patients, and primary culture cells were established from these tissues. Four major molecular subgroups were sorted from the primary culture: HER2 BCSCs (CD44CD24HER2), HER2 BCSCs (CD44CD24HER2), HER2 primary culture cells (CD44CD24HER2) and triple positive primary culture cells (CD44CD24HER2). These cells were cultured and treated with trastuzumab, paclitaxel, carboplatin, and the combination of those three drugs for 96 h. Cellular responses to these drugs were determined by XTT cytotoxicity test. MMPs and cytokine array analysis showed that MMPs and TIMP-1, TIMP-2 proteins were expressed more in HER2 BCSCs than in primary culture. HER2 BCSCs were more resistant to drugs than HER2 BCSCs. Our findings suggest that the presence of HER2 BCSCs may be responsible for primary trastuzumab resistance in HER2 BC cell population. Further studies investigating the function of MMPs are needed for drug targeting of BCSCs.
乳腺癌（BC）是女性癌症死亡的主要原因。据报道，BC 治疗失败的原因之一是化疗药物对乳腺癌干细胞样细胞（BCSCs）无效。HER2 受体在 BCSCs 的自我更新中起着重要作用。研究发现，BCSCs 中的基质金属蛋白酶（MMP）和细胞因子水平较高，这表明它们具有潜在的转移能力。因此，本研究旨在评估 BCSCs 对曲妥珠单抗的反应，并研究原发性乳腺癌细胞和 HER2 BCSCs 中的 MMP 水平。在手术干预期间从 10 名乳腺癌患者中获得肿瘤组织样本，并从这些组织中建立原代培养细胞。从原代培养中分离出四个主要的分子亚群：HER2 BCSCs（CD44CD24HER2）、HER2 BCSCs（CD44CD24HER2）、HER2 原代培养细胞（CD44CD24HER2）和三阳性原代培养细胞（CD44CD24HER2）。这些细胞被培养并分别用曲妥珠单抗、紫杉醇、卡铂以及这三种药物的组合处理 96 小时。通过 XTT 细胞毒性试验确定这些药物对细胞的反应。MMPs 和细胞因子阵列分析表明，MMPs 和 TIMP-1、TIMP-2 蛋白在 HER2 BCSCs 中的表达高于原代培养。HER2 BCSCs 比 HER2 原代培养细胞对药物更有抵抗力。我们的研究结果表明，HER2 BCSCs 的存在可能是 HER2 BC 细胞群体中曲妥珠单抗原发性耐药的原因。需要进一步研究 MMP 的功能，以针对 BCSCs 进行药物靶向治疗。
