Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4

Grottke, Astrid; Ewald, Florian; Lange, Tobias; Nörz, Dominik; Herzberger, Christiane; Bach, Johanna; Grabinski, Nicole; Gräser, Lareen; Höppner, Frank; Nashan, Björn; Schumacher, Udo; Jücker, Manfred

doi:10.1371/journal.pone.0146370

Cited by 63 publications

(61 citation statements)

References 54 publications

(80 reference statements)

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“…In this paper, the reduced proliferation was seen in two cell lines that exhibited the highest levels of Akt3 expression, suggesting that Akt3 ablation may be effective in a subset of ovarian cancers. Recently, it has been shown that downregulation of Akt3 in a human breast cancer cell line increased migration in vitro and led to greater lung metastases in vivo [34]. In our in vivo model, we found an increase in tumor cell proliferation in Akt3 knockdown tumors compared to controls, but again this increase was significantly less than that seen in Akt2 KD tumors.…”

Section: Discussionsupporting

confidence: 47%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

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Section: Discussionsupporting

confidence: 47%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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“…Unfortunately, frequent mutations or copy number changes in genes important for cell cycle arrest or apoptosis limit the antitumor activity of inhibitors of the PI3K/Akt pathway (Ma, 2015). The scenario is further complicated by the expression of all three Akt isoforms in cells with a triple-negative phenotype, with dissimilar effects on the metastatic process (Dillon et al, 2009;Grottke et al, 2016;Riggio et al, 2017), raising the problem of the identification of isoform-specific inhibitors to be selectively used in the different breast tumor subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, despite a promising chance, emerging data revealing different or even opposite functional roles of Akt isoforms in the regulation of proliferation, migration, and invasion (Dillon et al, 2009;Li et al, 2016;Riggio et al, 2017) opened the issue of the reliability of the use of pan or isoform-specific Akt inhibitors in the different tumor subtypes and of the combined use of inhibitors and cytotoxic chemotherapy. The development of Akt inhibitors is particularly problematic in triple-negative breast cancers (TNBC) that express all three Akt isoforms and show the highest activation of the Akt downstream pathways (Chin et al, 2014;Grottke et al, 2016;Massihnia et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Vav1 downmodulates Akt in different breast cancer subtypes: a new promising chance to improve breast cancer outcome

et al. 2018

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Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p‐Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumor‐derived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER‐negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p‐Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow‐up of patients with low p‐Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple‐negative phenotype, for which target‐based therapies are not currently available.

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“…Although AKT3 upregulation or increased copy number of its chromosomal region was reported in different cancers (46), recent data indicate that AKT3 inhibits cancer cell migration. It has been shown that knockdown of AKT3 increases the metastatic potential of tumor cells (47). Another gene is FMN2, a member of the formin homology protein family.…”

Section: Discussionmentioning

confidence: 99%

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Abbasi

Rifatbegovic

Brunner

et al. 2017

Clinical Cancer Research

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Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrowderived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32.Ó2017 AACR.

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Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4

Cited by 63 publications

References 54 publications

Akt isoform specific effects in ovarian cancer progression

Akt isoform specific effects in ovarian cancer progression

Vav1 downmodulates Akt in different breast cancer subtypes: a new promising chance to improve breast cancer outcome

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

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