Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan.
Int J Mol Med. 2023 Sep;52(3). doi: 10.3892/ijmm.2023.5283. Epub 2023 Jul 21.
Triple‑negative breast cancer (TNBC), a highly metastatic subtype of breast cancer, and it has the worst prognosis among all subtypes of breast cancer. However, no effective systematic therapy is currently available for TNBC metastasis. Therefore, novel therapies targeting the key molecular mechanisms involved in TNBC metastasis are required. The present study examined whether the expression levels of human epidermal growth factor receptor 3 (HER3) were associated with the metastatic phenotype of TNBC, and evaluated the potential of HER3 as a therapeutic target and . A new highly metastatic 4T1 TNBC cell line, termed 4T1‑L8, was established. The protein expression levels in 4T1‑L8 cells were measured using luminex magnetic bead assays and western blot analysis. The HER3 expression levels and distant metastasis‑free survival (DMFS) in TNBC were analyzed using Kaplan‑Meier Plotter. Transwell migration and invasion assays were performed to detect migration and invasion. The anti‑metastatic effects were determined in an experimental mouse model of metastasis. The results revealed that the increased expression of the HER3/Akt/mTOR pathway was associated with a greater level of cell migration, invasion and metastasis of TNBC cells. In addition, it was found that high expression levels of HER3 were associated with a poor DMFS. The inhibition of the HER3/Akt/mammalian target of rapamycin (mTOR) pathway decreased the migration, invasion and metastasis of TNBC cells by decreasing the expression of C‑X‑C chemokine receptor type 4 (CXCR4). Furthermore, treatment of metastatic TNBC cells with everolimus inhibited their migration, invasion and metastasis by decreasing CXCR4 expression. Thus, targeting the HER3/Akt/mTOR pathway opens up a new avenue for the development of therapeutics against TNBC metastasis; in addition, everolimus may prove to be an effective therapeutic agent for the suppression of TNBC metastasis.
三阴性乳腺癌（TNBC）是一种高度转移性的乳腺癌亚型，其预后在所有乳腺癌亚型中最差。然而，目前针对 TNBC 转移尚无有效的系统治疗方法。因此，需要针对涉及 TNBC 转移的关键分子机制的新型治疗方法。本研究探讨了人类表皮生长因子受体 3（HER3）的表达水平是否与 TNBC 的转移表型相关，并评估了 HER3 作为治疗靶点的潜力。建立了一种新的高转移性 4T1 TNBC 细胞系，称为 4T1-L8。使用 Luminex 磁珠分析和 Western blot 分析测量 4T1-L8 细胞中的蛋白表达水平。使用 Kaplan-Meier Plotter 分析 TNBC 中的 HER3 表达水平和无远处转移生存（DMFS）。进行 Transwell 迁移和侵袭实验以检测迁移和侵袭。在转移实验小鼠模型中确定了抗转移作用。结果表明，HER3/Akt/mTOR 通路的表达增加与 TNBC 细胞迁移、侵袭和转移的水平更高相关。此外，发现 HER3 高表达与 DMFS 不良相关。抑制 HER3/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路通过降低 C-X-C 趋化因子受体 4（CXCR4）的表达来降低 TNBC 细胞的迁移、侵袭和转移。此外，依维莫司治疗转移性 TNBC 细胞可通过降低 CXCR4 表达来抑制其迁移、侵袭和转移。因此，靶向 HER3/Akt/mTOR 通路为开发针对 TNBC 转移的治疗方法开辟了新途径；此外，依维莫司可能被证明是抑制 TNBC 转移的有效治疗剂。
