Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str., 115 27 Athens, Greece.
Department of Biology, University of Patras, 265 04 Patras, Greece.
Cells. 2023 Jul 17;12(14):1869. doi: 10.3390/cells12141869.
Breast cancer is one of the most lethal malignancies in women worldwide and is characterized by rapid growth and low survival rates, despite advances in tumor biology and therapies. Novel therapeutic approaches require new insights into the molecular mechanisms of malignant transformation and progression. To this end, here, we identified Prox1 as a negative regulator of proliferation and tumor-related metabolism in breast cancer. In particular, we showed that breast tumors from human patients exhibited reduced levels of Prox1 expression, while high expression levels of Prox1 were associated with a favorable prognosis in breast cancer patients. Moreover, we experimentally demonstrated that Prox1 was sufficient to strongly suppress proliferation, migration, and the Warburg effect in human breast cancer cells without inducing apoptosis. Most importantly, over-expression of Prox1 inhibited breast tumor growth in vivo in both heterotopic and orthotopic xenograft mouse models. The anti-tumorigenic effect of Prox1 was mediated by the direct repression of c-Myc transcription and its downstream target genes. Consistently, c-Myc over-expression from an artificial promoter that was not targeted by Prox1 reversed Prox1's anti-tumor effects. These findings suggest that Prox1 has a tumor suppressive role via direct transcriptional regulation of c-Myc, making it a promising therapeutic gene for breast cancer.
乳腺癌是全球女性中最致命的恶性肿瘤之一，其特征是生长迅速，存活率低，尽管肿瘤生物学和治疗方法取得了进展。新的治疗方法需要对恶性转化和进展的分子机制有新的认识。为此，在这里，我们确定 Prox1 是乳腺癌中增殖和与肿瘤相关的代谢的负调节剂。特别是，我们表明，来自人类患者的乳腺肿瘤表现出 Prox1 表达水平降低，而 Prox1 高表达水平与乳腺癌患者的良好预后相关。此外，我们通过实验证明 Prox1 足以强烈抑制人乳腺癌细胞的增殖、迁移和瓦伯格效应，而不会诱导细胞凋亡。最重要的是，Prox1 的过表达在异位和原位异种移植小鼠模型中均能抑制体内乳腺癌肿瘤的生长。Prox1 的抗肿瘤作用是通过直接抑制 c-Myc 转录及其下游靶基因来介导的。一致地，来自不受 Prox1 靶向的人工启动子的 c-Myc 过表达逆转了 Prox1 的抗肿瘤作用。这些发现表明，Prox1 通过对 c-Myc 的直接转录调控发挥肿瘤抑制作用，使其成为治疗乳腺癌的有前途的治疗基因。
