Breast cancer is one of the most common malignant tumors in women worldwide, and its high incidence and mortality rate seriously threaten women's health. Studies show that the forkhead box O3a (FoxO3a) plays a key role in the occurrence and progression of breast cancer, particularly in the regulation of apoptosis. As a major member of the FoxO family, FoxO3a exerts tumor-suppressive functions by participating in apoptosis regulation and cell-cycle control. In breast cancer cells, FoxO3a acts as a downstream signaling hub of multiple upstream pathways including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and serum- and glucocorticoid-regulated kinase 1 (SGK1). Through nucleocytoplasmic shuttling and alterations in transcriptional activity, FoxO3a precisely modulates the expression of apoptosis-related target genes such as Bcl-2-interacting mediator of cell death (Bim) and p53-upregulated modulator of apoptosis (PUMA), thereby influencing cell survival or death. In addition, multiple natural compounds and combination therapies can induce apoptosis in breast cancer cells by restoring or enhancing FoxO3a activity, and may partially overcome treatment resistance. Systematic elucidation of the complexity of the FoxO3a signaling network and its dual roles in breast cancer therapy may provide theoretical support for understanding tumor-drug resistance mechanisms and for developing precision therapeutic strategies targeting FoxO3a nodes. Future research should further clarify the functional differences among FoxO3a splice variants and FoxO family members, reveal the molecular basis of FoxO3a functional switching in the tumor microenvironment, and promote the clinical translation of biomarkers and targeted drugs.
乳腺癌是全球女性最常见的恶性肿瘤之一，其高发病率及高病死率严重威胁女性健康。研究表明转录因子叉头框蛋白O(forkhead box O，FoxO)3a在乳腺癌的发生、发展中扮演关键角色，尤其在调控细胞凋亡中具有重要功能。FoxO3a是FoxO家族的重要成员，通过调控细胞凋亡和细胞周期等过程发挥肿瘤抑制作用。在乳腺癌细胞中，FoxO3a作为磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B，PI3K/Akt)、丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)、血清和糖皮质激素诱导蛋白激酶1(serum and glucocorticoid regulated kinase 1，SGK1)等上游通路的下游枢纽，通过核质穿梭及转录活性变化，精细调控Bcl-2相互作用介导的细胞死亡蛋白(Bcl-2 interacting mediator of cell death，Bim)、p53上调的凋亡调节因子(p53 upregulated modulator of apoptosis，PUMA)等凋亡相关靶基因的表达，影响细胞的生存或死亡。此外，多种天然化合物及联合治疗可通过恢复或增强FoxO3a活性诱导乳腺癌细胞凋亡，并在一定程度上克服耐药。系统揭示FoxO3a信号网络的复杂性及其在乳腺癌治疗中的双重角色，可为理解肿瘤耐药机制及制订以FoxO3a为靶标的精准治疗策略提供关键理论依据。未来研究应进一步明确FoxO3a不同剪接变体及FoxO家族成员的功能差异，解析其在肿瘤微环境中功能转换的分子机制，并推动基于FoxO3a通路活性的生物标志物及靶向药物的临床转化。.
Keywords: FoxO3a; breast cancer; cell apoptosis; protein-protein interaction network; signaling pathway.