PART1调控基底细胞样型乳腺癌脑转移的分子机制

The brain metastasis of basal-like breast cancer is a frustrating clinical challenge. However, the specific mechanism underlying the brain metastasis of basal-like breast cancer remains not determined yet, and effective targeted therapeutic strategy is still lacking. Our preliminary research results found that expression levels of long non-coding RNA - prostate androgen-regulated transcript 1 (PART1) was specifically upregulated in basal-like breast cancer, which predicted high risk in basal-like breast cancer patients with brain metastasis. Upregulating PART1 promoted brain metastasis in basal-like breast cancer cells in vivo; conversely, silencing PART1 yielded an opposite effect on basal-like breast cancer cells. In experiments in vitro, our results further revealed that both androgen receptor (AR) and MAF BZIP Transcription Factor K (MAFK) upregulated PART1 expression, which promoted cancer cells self-renewal, anoikis resistance and constitutive activation of AR signaling through sponging tumor suppressive miR-30a-3p/-5p and miR-433-3p, resulting in brain metastasis of basal-like breast cancer. However, the specific mechanism remains further investigated. Next, we will investigate the specific functions and mechanisms in each process of brain metastasis in basal-like breast cancer by cell, animal and half-vivo model; we will further utilize versatile molecular biological techniques to clarify the molecular mechanism responsible for the cause of PART1 overexpression, and the one for constitutive activation of AR signaling; finally. Accordingly, the successful implementation of this project will provide novel auxiliary diagnostic molecule and potential therapeutic target to conquer the brain metastasis of basal-like breast cancer.

基底细胞样型（BasL）乳腺癌脑转移是困扰临床的难题，其机制不明确，缺少有效的早期诊断及治疗方法。本项目预实验发现，长链非编码RNA-前列腺雄激素调控转录本1（PART1）在BasL乳腺癌中特异性高表达，预示着患者更高的脑转移风险。体内实验中，上调PART1能促进癌细胞的脑转移，下调则抑制。体外实验中，PART1受雄激素受体（AR）和转录因子MAFK调控，通过吸附抑癌的miR-30a-3p/-5p和miR-433-3p，促进癌细胞的自我更新、抗失巢凋亡等能力并维持AR的激活，参与了BasL乳腺癌脑转移，但具体的机制尚待进一步探索。本课题拟利用细胞、动物及半体内模型，探讨PART1在BasL乳腺癌脑转移各阶段的具体分子机制；利用多种分子生物学技术及临床样品检测，阐明PART1异常表达的原因，及其维持AR持续性激活的分子机制。为临床BasL乳腺癌脑转移的诊治提供新的生物标记物及潜在的治疗靶点。

基底细胞样型（BasL）乳腺癌是根据基因表达谱特征进行分类的一种乳腺癌亚型，临床特征、生物学行为和分子标记与三阴乳腺癌（TNBC）高度重合。BasL型乳腺癌脑转移是困扰临床的难题，其相关驱动机制不明确，缺少有效的早期诊断及治疗方法。本项目的前期工作中发现，长链非编码RNA-前列腺雄激素调控转录本1（PART1）在BasL乳腺癌中特异性高表达，预示着患者更高的脑转移风险。而在本项目进行过程中，本研究团队发现：（1）PART1的过表达能促进BasL乳腺癌细胞体外的自我更新和抗失巢凋亡，增强其对脑血管屏障的粘附及侵出，增强其对脑部微环境的适应，最终促进癌细胞的脑转移。（2）PART1在BasL乳腺癌中高表达的可能机制是MAFK扩增导致的转录上调，过表达的PART1能通过解除miR-30a-3p/-5p和miR-433-3p对下游基因（AKT3、CREB1、SMAD2和TEAD1等）的抑制作用，由此促进了癌细胞的脑转移。（3）靶向抑制PART1能显著抑制癌细胞在动物体内的脑转移，临床样品的分析发现，PART1的表达与乳腺癌脑转移预后相关，具有作为辅助诊断标志物的开发前景。本课题的研究发现，对阐明BasL乳腺癌的脑转移有一定的理论意义，并有继续开发的潜在价值。