Akt Isoforms: A Family Affair in Breast Cancer

Basu, Alakananda; Lambring, Christoffer

doi:10.3390/cancers13143445

Cited by 38 publications

(25 citation statements)

References 169 publications

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“…Akt is hyperactivated in most breast cancers and, in recent years, several inhibitors that block the phosphorylation of the enzyme have been identified, despite the high homology among the Akt isozymes which made it difficult to develop isoform-specific drugs [ 33 ]. In breast tumors as in other cancers, growing evidence shows distinct and perhaps opposite oncogenic functions of Akt isozymes, the expression of which may also vary in primary and secondary sites of tumors [ 11 , 15 ]. Based on the need of precise isoform-specific inhibitors, especially in the treatment of the most aggressive breast cancers, the role of Vav1 as a potential down-regulator of individual Akt isozymes was investigated in the MDA-MB-231 cell line, highly invasive and with a triple negative phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperactivation of Akt signaling is a central event in human cancer and almost 30% of TNBCs have alterations in the PI3K/Akt/mTOR pathway [ 7 , 8 ]. The Akt family includes three members (Akt1, Akt2 and Akt3) that play distinct roles in breast cancer malignancy, being Akt1 correlated with proliferation of tumor cells and the other two isozymes variously involved in invasion/metastasis [ 9 , 10 , 11 ]. In tumors with a triple negative phenotype, Akt2 has a crucial role in metastasis by regulating the epithelial-to-mesenchymal-transition (EMT) and by enabling extravasation through the vessel wall [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

Grassilli

Brugnoli

Cairo

et al. 2022

JPM

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Grassilli

Brugnoli

Cairo

et al. 2022

JPM

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“…Drago-Ferrante and colleagues demonstrated that miR-29b1-5p expression is strongly down-regulated in TNBC tissues and cell lines and this impacts on proliferation and migration of TNBC-derived cells [ 24 ]. They found that the over-expression of miR-29b1-5p in MDA-MB-231 cells decreases in vitro growth rate, Ki-67 levels, and migration [ 24 ], and the decrease of Wnt/βcatenin and Akt-signaling pathways, both involved in tumorigenesis and progression of breast cancer [ 74 , 75 ]. In addition, it was demonstrated that miR-29b1-5p down-modulates, at both mRNA and protein levels, spindlin 1 (SPIN1), which enables methylated histone binding activity and participates in PI3K/Akt-mediated chemoresistance of metastatic breast cancer [ 24 , 76 ].…”

Section: Roles Of Mir-29b In Breast Cancermentioning

confidence: 99%

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

2022

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The miR-29 family comprises miR-29a, miR-29b, and miR-29c, and these molecules play crucial and partially overlapped functions in solid tumors, in which the different isoforms are variously de-regulated and mainly correlated with tumor suppression. miR-29b is the most expressed family member in cancer, in which it is involved in regulating gene expression at both transcriptional and post-transcriptional levels. This review focuses on the role of miR-29b in breast cancer, in which it plays a controversial role as tumor suppressor or onco-miRNA. Here we have highlighted the dual effect of miR-29b on breast tumor features, which depend on the prevailing function of this miRNA, on the mature miR-29b evaluated, and on the breast tumor characteristics. Remarkably, the analyzed miR-29b form emerged as a crucial element in the results obtained by various research groups, as the most abundant miR-29b-3p and the less expressed miR-29b1-5p seem to play distinct roles in breast tumors with different phenotypes. Of particular interest are the data showing that miR-29b1-5p counteracts cell proliferation and migration and reduces stemness in breast tumor cells with a triple negative phenotype. Even if further studies are required to define exactly the role of each miR-29b, our review highlights its possible implication in phenotype-specific management of breast tumors.

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“…AKT isoforms can specifically regulate several cellular processes. While all isoforms seem to downregulate autophagy, AKT1 and AKT3 seem to be involved in cell proliferation and AKT1 and AKT2 in the regulation of the cancer cell metabolism [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

Azzalini

Tierno

Bartoletti

et al. 2022

Cancers

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High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients’ outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients’ survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.

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Akt Isoforms: A Family Affair in Breast Cancer

Cited by 38 publications

References 169 publications

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

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

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

AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

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