Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Cell Death Dis. 2023 Apr 18;14(4):272. doi: 10.1038/s41419-023-05746-8.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast neoplasms with a higher risk of recurrence and metastasis than non-TNBC. Nevertheless, the factors responsible for the differences in the malignant behavior between TNBC and non-TNBC are not fully explored. Proline rich 15 (PRR15) is a protein involved in the progression of several tumor types, but its mechanisms are still controversial. Therefore, this study aimed to investigate the biological role and clinical applications of PRR15 on TNBC. PRR15 gene was differentially expressed between TNBC and non-TNBC patients, previously described as an oncogenic factor in breast cancer. However, our results showed a decreased expression of PRR15 that portended a favorable prognosis in TNBC rather than non-TNBC. PRR15 knockdown facilitated the proliferation, migration, and invasive ability of TNBC cells in vitro and in vivo, which was abolished by PRR15 restoration, without remarkable effects on non-TNBC. High-throughput drug sensitivity revealed that PI3K/Akt signaling was involved in the aggressive properties of PRR15 silencing, which was confirmed by the PI3K/Akt signaling activation in the tumors of PRR15 patients, and PI3K inhibitor reversed the metastatic capacity of TNBC in mice. The reduced PRR15 expression in TNBC patients was positively correlated with more aggressive clinicopathological characteristics, enhanced metastasis, and poor disease-free survival. Collectively, PRR15 down-regulation promotes malignant progression through the PI3K/Akt signaling in TNBC rather than in non-TNBC, affects the response of TNBC cells to antitumor agents, and is a promising indicator of disease outcomes in TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，其复发和转移风险高于非三阴性乳腺癌。然而，导致 TNBC 和非 TNBC 恶性行为差异的因素尚未完全探索。富含脯氨酸 15（PRR15）是一种参与多种肿瘤类型进展的蛋白质，但它的机制仍存在争议。因此，本研究旨在探讨 PRR15 在 TNBC 中的生物学作用及其临床应用。PRR15 基因在 TNBC 和非 TNBC 患者之间存在差异表达，先前被描述为乳腺癌的致癌因子。然而，我们的研究结果显示，PRR15 的表达降低预示着 TNBC 患者的预后良好，而非非 TNBC。PRR15 敲低促进了 TNBC 细胞在体外和体内的增殖、迁移和侵袭能力，而 PRR15 的恢复则消除了这种作用，对非 TNBC 没有明显影响。高通量药物敏感性试验显示，PI3K/Akt 信号通路参与了 PRR15 沉默的侵袭特性，这在 PRR15 患者的肿瘤中得到了证实，并且 PI3K 抑制剂逆转了 TNBC 在小鼠中的转移能力。TNBC 患者中 PRR15 表达降低与更具侵袭性的临床病理特征、增强的转移和不良的无病生存相关。综上所述，PRR15 的下调通过 PI3K/Akt 信号通路促进 TNBC 中的恶性进展，而不是在非 TNBC 中，影响 TNBC 细胞对抗肿瘤药物的反应，是 TNBC 疾病结局的一个有前途的指标。
