PO.ET02.07 · 实验与分子治疗
CCN5通过Merlin/NF2和Orai-1分子特征介导三阴性乳腺癌生长和转移的抑制
Triple-negative breast cancer growth and metastasis suppression by CCN5 is mediated by Merlin/NF2 and Orai-1 molecular signatures
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摘要 Abstract
中文摘要
乳腺癌(BC)是美国及全球女性癌症相关死亡的第二大原因。这一疾病影响约八分之一的女性(约12%)，几乎波及全世界的每一个家庭。这些统计数据对美国女性退伍军人同样具有相关性。目前针对BC的疗法被认为可改善患者生存；然而，三分之一患有侵袭性三阴性乳腺癌(TNBC)的患者与激素受体阳性亚型患者相比可能经历更频繁的复发，并最终可能发展为远处转移性疾病。目前，尚无针对侵袭性和转移性乳腺癌的靶向疗法，凸显了改善治疗选择的迫切需求。TNBC是一种异质性的细胞混合体，肿瘤间和肿瘤内均存在显著变异性，这往往使治疗方案的效果降低。一种不同于现有治疗策略的新方法可能对BC的临床研究设计和未来实践产生积极影响，有望增加TNBC幸存者的数量。我们既往的研究在一大批原发性BC样本和细胞系中检测了CCN5表达，发现CCN5表达在大多数样本中与疾病呈负相关。在本研究中，我们证明CCN5在基因工程小鼠模型(GEMMs)和人TNBC异种移植模型中抑制肿瘤生长和转移扩散，且不引起任何副作用。CCN5可能通过调控TNBC细胞中Merlin(一种抑癌基因)和Orai1(一种参与转移的基因)的表达和活性来促成这些关键过程。此外，CCN5抑制JunB/AP-1转录因子和VEGF-A，同时防止ZO-1丢失(ZO-1是VEGF-A的下游靶点，也是一种作为转移屏障的蛋白)，这与内皮细胞(EC)单层中通透性的阻断相一致。这些综合发现提示，CCN5通过调控多个基因特征来预防或延缓TNBC细胞的生长、侵袭和转移。因此，CCN5治疗或恢复可能代表一种有前景的乳腺癌新型治疗干预手段。(本研究由VA Merit基金资助)
查看英文原文 English abstract
Breast cancer (BC) is the second leading cause of cancer-related death among women, both in the United States and globally. This disease affects approximately one in eight women (around 12%), impacting nearly every family worldwide. The statistics are similarly relevant for female U.S. veterans. Current therapies for BC are thought to improve patient survival; however, one-third of patients with aggressive triple-negative breast cancer (TNBC) may experience more frequent relapses compared to those with hormone receptor-positive subtypes, and may eventually develop distant metastatic disease. Currently, there are no targeted therapies available for invasive and metastatic breast cancer, highlighting a critical need for improved treatment options. TNBC is a heterogeneous mix of cells, with significant variability both between and within tumors, which often makes therapeutic regimens less effective. A novel approach, diverging from existing treatment strategies, could positively influence both clinical study designs and future practices in BC, potentially increasing the number of TNBC survivors. Our previous studies examined CCN5 expression in a large cohort of primary BC samples and cell lines, finding that CCN5 expression is inversely correlated with disease in most samples. In this study, we demonstrated that CCN5 inhibits tumor growth and metastatic spread in genetically engineered mouse models (GEMMs) and human TNBC xenograft models, without causing any side effects. CCN5 may facilitate these critical processes by regulating the expression and activity of Merlin (a tumor suppressor gene) and Orai1 (a gene involved in metastasis) in TNBC cells. In addition, CCN5 suppresses the JunB/AP-1 transcription factor and VEGF-A, while protecting against ZO-1 loss (a downstream target of VEGF-A and a protein that acts as a barrier to metastasis), mirroring the blockade of permeability in endothelial cell (EC) monolayers. These collective findings suggest that CCN5 prevents or delays the growth, invasion, and metastasis of TNBC cells by regulating multiple gene signatures. Therefore, CCN5 treatment or restoration may represent a promising novel therapeutic intervention for breast cancer. (This work is supported by the VA Merit grants)
利益披露 Disclosure
I. Haque, None..
G. Maity, None..
J. L. Porter, None..
S. Banerjee, None..
S. K. Banerjee, None.