Grassilli Silvia, Brugnoli Federica, Cairo Stefano, Bianchi Nicoletta, Judde Jean-Gabriel, Bertagnolo Valeria
Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
LTTA Centre, University of Ferrara, 44121 Ferrara, Italy.
J Pers Med. 2022 Jun 17;12(6):993. doi: 10.3390/jpm12060993.
Triple negative breast cancer (TNBC) represents the most aggressive breast tumor, showing a high intrinsic variability in terms of both histopathological features and response to therapies. Blocking the Akt signaling pathway is a well-studied approach in the treatment of aggressive breast tumors. The high homology among the Akt isoforms and their distinct, and possibly opposite, oncogenic functions made it difficult to develop effective drugs. Here we investigated the role of Vav1 as a potential down-regulator of individual Akt isozymes. We revealed that the over-expression of Vav1 in triple negative MDA-MB-231 cells reduced only the Akt2 isoform, acting at the post-transcriptional level through the up-modulation of miR-29b. The Vav1/miR-29b dependent decrease in Akt2 was correlated with a reduced lung colonization of circulating MDA-MB-231 cells. In cell lines established from PDX, the Vav1 induced down-modulation of Akt2 is strongly dependent on miR-29b and occurs only in some TNBC tumors. These findings may contribute to better classify breast tumors having the triple negative phenotype, and suggest that the activation of the Vav1/miR-29b axis, precisely regulating the amount of an Akt isozyme crucial for tumor dissemination, could have great potential for driving more accurate therapies to TNBCs, often not eligible or resistant to treatments.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺肿瘤，在组织病理学特征和对治疗的反应方面表现出高度的内在变异性。阻断Akt信号通路是治疗侵袭性乳腺肿瘤的一种研究充分的方法。Akt亚型之间的高度同源性及其独特的、可能相反的致癌功能使得开发有效的药物变得困难。在这里，我们研究了Vav1作为单个Akt同工酶潜在下调因子的作用。我们发现，Vav1在三阴性MDA-MB-231细胞中的过表达仅降低了Akt2亚型，通过上调miR-29b在转录后水平发挥作用。Vav1/miR-29b依赖性的Akt2减少与循环MDA-MB-231细胞的肺定植减少相关。在从人源肿瘤异种移植（PDX）建立的细胞系中，Vav1诱导的Akt2下调强烈依赖于miR-29b，并且仅在一些TNBC肿瘤中发生。这些发现可能有助于更好地对具有三阴性表型的乳腺肿瘤进行分类，并表明激活Vav1/miR-29b轴，精确调节对肿瘤播散至关重要的Akt同工酶的量，可能具有推动针对TNBCs进行更精确治疗的巨大潜力，TNBCs通常不符合治疗条件或对治疗耐药。
