Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

Abstract

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.

In‐silico and in‐vitro evidence suggest LINC01405 as a sponge for miR‐29b and miR‐497‐5p, and a potential regulator of Wnt, PI3K, and TGFB signaling pathways in breast carcinoma

“…MiR‐29b has been demonstrated to suppress tumor growth by targeting the AKT2 isoform. 29 Our study found upregulation of AKT1 and AKT3, which are involved in the signaling pathway of PI3K, and previous studies have demonstrated overactivation of the PI3K pathway in breast cancer. The enhanced mTOR expression, induced by miR‐29b and miR‐497, may result from AKT overexpression and phosphorylation.…”

“…Further evidence of LINC01405's ability to act as a scavenger was provided when we observed a significant rise in the expression of essential target genes for both miRNAs. MiR‐29b has been demonstrated to suppress tumor growth by targeting the AKT2 isoform 29 . Our study found upregulation of AKT1 and AKT3, which are involved in the signaling pathway of PI3K, and previous studies have demonstrated overactivation of the PI3K pathway in breast cancer.…”

Mir-29b in Breast Cancer: A Promising Target for Therapeutic Approaches

“…Furthermore, the up-regulation of miR-29b reduces cell proliferation and induces the apoptosis of MCF7 cells by regulating the expression of STAT3 [ 54 ]. It has been recently demonstrated that, in certain molecular subtypes of triple-negative breast breast tumor cells, miR-29b-3p down-modulates Akt2, a member of the Akt family mainly involved in migration and metastasis of breast cancer, and prevents the in vivo lung colonization of MDA-MB-231 cells [ 73 ].…”