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AKT1 Transcriptomic Landscape in Breast Cancer Cells.

ABSTRACT: Overexpression and hyperactivation of the serine/threonine protein kinase B (AKT) pathway is one of the most common cellular events in breast cancer progression. However, the nature of AKT1-specific genome-wide transcriptomic alterations in breast cancer cells and breast cancer remains unknown to this point. Here, we delineate the impact of selective AKT1 knock down using gene-specific siRNAs or inhibiting the AKT activity with a pan-AKT inhibitor VIII on the nature of transcriptomic changes in breast cancer cells using the genome-wide RNA-sequencing analysis. We found that changes in the cellular levels of AKT1 lead to changes in the levels of a set of differentially expressed genes and, in turn, imply resulting AKT1 cellular functions. In addition to an expected positive relationship between the status of AKT1 and co-expressed cellular genes, our study unexpectedly discovered an inherent role of AKT1 in inhibiting the expression of a subset of genes in both unstimulated and growth factor stimulated breast cancer cells. We found that depletion of AKT1 leads to upregulation of a subset of genes-many of which are also found to be downregulated in breast tumors with elevated high AKT1 as well as upregulated in breast tumors with no detectable AKT expression. Representative experimental validation studies in two breast cancer cell lines showed a reasonable concurrence between the expression data from the RNA-sequencing and qRT-PCR or data from ex vivo inhibition of AKT1 activity in cancer patient-derived cells. In brief, findings presented here provide a resource for further understanding of AKT1-dependent modulation of gene expression in breast cancer cells and broaden the scope and significance of AKT1 targets and their functions.

SUBMITTER: George B

PROVIDER: S-EPMC9332453 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy and defining driver events.Here, we applied a powerful integrative network algorithm to matched DNA methylation and RNA-Seq data for 724 estrogen receptor (ER)-positive (ER+) breast cancers and 111 normal adjacent tissue specimens from The Cancer Genome Atlas (TCGA) project, in order to identify putative epigenetic driver events and to explore the resulting molecular taxonomy. This revealed the existence of nine functionally deregulated epigenetic hotspots encompassing a total of 146 genes, which we were able to validate in independent data sets encompassing over 1000 ER+ breast cancers. Integrative clustering of the matched messenger RNA (mRNA) and DNA methylation data over these genes resulted in only two clusters, which correlated very strongly with the luminal-A and luminal B subtypes. Overall, luminal-A and luminal-B breast cancers shared the same epigenetically deregulated hotspots but with luminal-B cancers exhibiting increased aberrant DNA methylation patterns relative to normal tissue. We show that increased levels of DNA methylation and mRNA expression deviation from the normal state define a marker of poor prognosis. Our data further implicates epigenetic silencing of WNT signalling antagonists and bone morphogenetic proteins (BMP) as key events underlying both luminal subtypes but specially of luminal-B breast cancer. Finally, we show that DNA methylation changes within the identified epigenetic interactome hotspots do not exhibit mutually exclusive patterns within the same cancer sample, instead exhibiting coordinated changes within the sample.Our results indicate that the integrative DNA methylation and transcriptomic landscape of ER+ breast cancer is surprisingly homogeneous, defining two main subtypes which strongly correlate with luminal-A/B subtype status. In particular, we identify WNT and BMP signalling as key epigenetically deregulated tumour suppressor pathways in luminal ER+ breast cancer, with increased deregulation seen in luminal-B breast cancer.

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AKT1 Transcriptomic Landscape in Breast Cancer Cells.

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