Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
Clin Transl Med. 2024 Nov;14(11):e70097. doi: 10.1002/ctm2.70097.
Triple-negative breast cancer (TNBC) is distinguished by a significant likelihood of distant recurrence and an unfavourable prognosis. However, the underlying molecules and mechanisms have not been fully elucidated.
We investigated the expression profile and clinical relevance of chaperonin-containing TCP1 subunit 6A (CCT6A) in TNBC. We performed cell function assays on TNBC cells with CCT6A knockdown or overexpression. To further explore the mechanism of action of CCT6A, RNA sequencing and co-immunoprecipitation-mass spectrometry analyses were utilized. Rescue and ubiquitination assays evaluated the impact of TRIM21-mediated CCT6A ubiquitination and degradation on TNBC progression in vitro and in vivo. Finally, we studied the potential of Ipatasertib, a pharmacological AKT inhibitor, and/or anti-PD1 therapy in inhibiting TNBC progression.
Elevated CCT6A expression in TNBC patients was associated with an adverse prognosis and lymph node metastasis. Mechanistically, CCT6A facilitated cell migration, invasion, epithelial-mesenchymal transition and proliferation by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The TRIM21 RING domain is an E3 ligase, facilitating the K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Moreover, in the tumour tissues of the CCT6A-overexpressing mice, the quantity of CD8+ T cells and the concentration of secreted interferon-gamma were decreased, whereas in the group double-overexpression of CCT6A and TRIM21, they were elevated; the opposite was observed in the knockdown and double-knockdown groups. Ipatasertib demonstrated enhanced efficacy in inhibiting cell proliferation, invasion and migration in TNBC cells ectopically expressing CCT6A. When Ipatasertib and anti-PD1 therapies were combined, both the tumour volume and mass exhibited a notable reduction, while the expression of CD45+CD8+ T cells increased, and that of CD45+CD4+CTLA4+ and CD45+CD4+PD1+ T cells decreased.
Our findings indicate that TRIM21 inhibits TNBC progression by facilitating the K48-linked ubiquitination-mediated degradation of CCT6A via the PI3K/AKT signalling pathway. This highlights the potential of Ipatasertib and/or anti-PD1 as therapeutic strategies, particularly for TNBC patients overexpressing CCT6A.
Chaperonin TCP1 subunit 6A (CCT6A) plays an oncogenic role in triple-negative breast cancer (TNBC) through the AKT signaling pathway. TRIM21 facilitated K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Our study collectively underscores the potential of Ipatasertib in conjunction with anti-PD1 therapy as a promising strategy to counteract CCT6A/AKT hyperactivity-driven TNBC progression.
三阴性乳腺癌（TNBC）具有远处复发和预后不良的显著可能性。然而，其潜在的分子和机制尚未完全阐明。
我们研究了伴侣蛋白包含 TCP1 亚基 6A（CCT6A）在 TNBC 中的表达谱和临床相关性。我们对 CCT6A 敲低或过表达的 TNBC 细胞进行了细胞功能测定。为了进一步探讨 CCT6A 的作用机制，我们进行了 RNA 测序和免疫共沉淀-质谱分析。挽救和泛素化测定评估了 TRIM21 介导的 CCT6A 泛素化和降解对 TNBC 体外和体内进展的影响。最后，我们研究了伊帕替尼（一种药理学 AKT 抑制剂）和/或抗 PD1 治疗抑制 TNBC 进展的潜力。
TNBC 患者中 CCT6A 的高表达与不良预后和淋巴结转移相关。在机制上，CCT6A 通过激活磷脂酰肌醇 3-激酶（PI3K）/AKT 通路促进细胞迁移、侵袭、上皮-间充质转化和增殖。TRIM21 的 RING 结构域是一种 E3 连接酶，促进 CCT6A 的 K48 连接泛素化介导的降解，从而阻碍 TNBC 的进展。此外，在 CCT6A 过表达小鼠的肿瘤组织中，CD8+T 细胞数量和分泌的干扰素-γ浓度降低，而在 CCT6A 和 TRIM21 双重过表达组中，它们升高；在敲低和双重敲低组中观察到相反的情况。伊帕替尼增强了 TNBC 细胞中过表达 CCT6A 的细胞增殖、侵袭和迁移的抑制作用。当伊帕替尼和抗 PD1 治疗联合使用时，肿瘤体积和质量均显著减少，而 CD45+CD8+T 细胞的表达增加，CD45+CD4+CTLA4+和 CD45+CD4+PD1+T 细胞的表达减少。
我们的研究结果表明，TRIM21 通过促进 PI3K/AKT 信号通路中 CCT6A 的 K48 连接泛素化介导的降解来抑制 TNBC 的进展。这凸显了伊帕替尼和/或抗 PD1 作为治疗策略的潜力，特别是对于 CCT6A 过表达的 TNBC 患者。
伴侣蛋白包含 TCP1 亚基 6A（CCT6A）通过 AKT 信号通路在三阴性乳腺癌（TNBC）中发挥致癌作用。TRIM21 促进 CCT6A 的 K48 连接泛素化介导的降解，从而阻碍 TNBC 的进展。我们的研究共同强调了伊帕替尼联合抗 PD1 治疗作为一种有前途的策略来对抗 CCT6A/AKT 活性驱动的 TNBC 进展的潜力。
