Highlights of This Issue

Abstract

Epigenetic cancer drivers represent a widely unexplored territory with a high potential for finding theranostic targets. Horie and colleagues combined the powers of promoter resolution Cap Analysis of Gene Expression (CAGE) data from the FANTOM5 consortium with RNA-seq and DNA-methylation data from The Cancer Genome Atlas (TCGA) project and reported a number of epigenetically regulated genes in non-small cell lung cancer (NSCLC); such genes may complement the known mutational drivers. The data also demonstrate that multiple DNA repeats of the REP522 family are epigenetically activated in NSCLC cells and act as promoters for cancer-specific lncRNAs such as RP1-90G24.10, AL022344.4, and PCAT7.Synonymous mutations do not change a protein sequence but can have wide-ranging effects on protein expression, and evidence indicates that synonymous mutations are enriched in tumors. However, previous studies have generally failed to determine whether these mutations have functional effects. In the current Rapid Impact, Bhagavatula and colleagues develop a massively parallel fluorescence assay to measure the effects of synonymous mutations in exon 6 of the tumor suppressor gene TP53, and identify several mutations that cause decreased protein expression due to splicing defects. This methodology suggests a general framework to assay synonymous mutations for their functional role in oncogenesis.Interferon signaling has been shown to be critical in immune-mediated elimination of early malignancies. Here, Walter and colleagues have identified a novel subset of genes, normally produced during active interferon signaling (interferon-stimulated genes, ISG), to be transcriptionally repressed by the progesterone receptor (PR) in both breast cancer cells and patient specimens. PR modulation of interferon transcriptional machinery and subsequent down-regulation of ISG expression represents a mechanism by which early malignant breast lesions evade immunosurveillance processes and progress to clinically relevant tumors.Inhibition of ciliogenesis is common in breast cancers. In this study, it is demonstrated that inhibition of ciliogenesis leads to earlier tumor formation, faster tumor growth, higher grade tumors, and increased metastasis. Furthermore, it is revealed that inhibition of ciliogenesis results in increased expression of Hedgehog-target genes through cross-talk with the TGF-alpha signaling pathway. Activation of the Hedgehog pathway is most frequently observed in the triple-negative breast cancer (TNBC) subtype and is associated with decreased overall survival. These mechanistic insights into how Hedgehog signaling is activated open the door to novel strategies to treat this aggressive form of breast cancer.