Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
Nutrients. 2019 Mar 14;11(3):624. doi: 10.3390/nu11030624.
Resistance to both chemotherapy and radiation therapy is frequent in triple-negative breast cancer (TNBC) patients. We established treatment-resistant TNBC MDA-MB-231/IR cells by irradiating the parental MDA-MB-231 cells 25 times with 2 Gy irradiation and investigated the molecular mechanisms of acquired resistance. The resistant MDA-MB-231/IR cells were enhanced in migration, invasion, and stem cell-like characteristics. Pathway analysis by the Database for Annotation, Visualization and Integrated Discovery revealed that the NF-κB pathway, TNF signaling pathway, and Toll-like receptor pathway were enriched in MDA-MB-231/IR cells. Among 77 differentially expressed genes revealed by transcriptome analysis, 12 genes involved in drug and radiation resistance, including interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were identified. We found that baicalein effectively reversed the expression of IFIT2, which is reported to be associated with metastasis, recurrence, and poor prognosis in TNBC patients. Baicalein sensitized radio- and chemoresistant cells and induced apoptosis, while suppressing stem cell-like characteristics, such as mammosphere formation, side population, expression of Oct3/4 and ABCG2, and CD44CD24 population in MDA-MB-231/IR cells. These findings improve our understanding of the genes implicated in radio- and chemoresistance in breast cancer, and indicate that baicalein can serve as a sensitizer that overcomes treatment resistance.
三阴性乳腺癌（TNBC）患者对化疗和放疗均有耐药性。我们通过用 2Gy 照射 25 次照射亲本 MDA-MB-231 细胞，建立了治疗耐药性的 TNBC MDA-MB-231/IR 细胞，并研究了获得性耐药的分子机制。耐药的 MDA-MB-231/IR 细胞在迁移、侵袭和干细胞样特征方面得到增强。通过数据库注释、可视化和综合发现分析，发现 NF-κB 通路、TNF 信号通路和 Toll 样受体通路在 MDA-MB-231/IR 细胞中富集。转录组分析揭示了 77 个差异表达基因，其中 12 个基因与药物和辐射耐药性有关，包括干扰素诱导的四肽重复蛋白 2（IFIT2）。我们发现黄芩素能有效逆转 IFIT2 的表达，IFIT2 被报道与 TNBC 患者的转移、复发和预后不良有关。黄芩素增敏放射和化学耐药细胞，并诱导细胞凋亡，同时抑制 MDA-MB-231/IR 细胞的干细胞样特征，如乳腺球体形成、侧群、Oct3/4 和 ABCG2 的表达以及 CD44CD24 群体。这些发现提高了我们对乳腺癌中涉及放射和化学耐药性的基因的认识，并表明黄芩素可以作为一种增敏剂，克服治疗耐药性。
