Elucidating feed-forward apoptosis signatures in breast cancer datasets: Higher FOS expression associated with a better outcome.

Overstimulation of pro-proliferative pathways and high level expression of pro-proliferative transcription factors (TFs) can lead to apoptosis. This is likely due to TF binding sites for pro-proliferative TFs common to pro-proliferative and pro-apoptosis-effector genes. Certain clinical datasets have indicated that molecular markers associated with higher proliferation rates lead to improved outcomes for patients with cancer. These observations have been extensively assessed on a general basis, however there has been little work dissecting feed-forward apoptosis signaling pathways that may represent specific distinctions between a pro-proliferative mechanism and a pro-apoptotic mechanism in samples from patients with cancer. Using The Cancer Genome Atlas datasets and bioinformatic approaches, the present study reports that higher FOS expression levels, along with higher FOS target apoptosis-effector gene expression, is associated with an increased survival, while higher POU2F1 expression is associated with a reduced survival (average difference of 25.9 months survival). In summary, in the datasets examined FOS represents an apoptosis-driver and high POU2F1 represents a driver mechanism for cancer development.

Identification of specific feed-forward apoptosis mechanisms and associated higher survival rates for low grade glioma and lung squamous cell carcinoma.

The mechanisms of cell proliferation due to the overexpression of certain transcription factors (TFs) have been well documented in the cancer setting. However, many of these same TFs have pro-apoptotic effects, particularly when expressed or activated at high levels, a process referred to as feed-forward apoptosis (FFA). To determine whether cancers could be stratified on the basis of specific FFA signatures, RNASeq data representing samples from the cancer genome atlas were analyzed, revealing that high expression of the pro-proliferative TFs, MYC and YY1, is associated with a favorable outcome in low-grade glioma (LGG) and lung squamous cell carcinoma (LUSC), respectively. Analysis of the RNASeq data also led to the identification of specific apoptosis-effector genes whose expression levels correlate with increased survival rates, for both LGG and LUSC. Although FFA has been demonstrated as a general effect in cancer, in this report, for the first time, results identify specific TFs and their responsive effector genes that distinguish subsets of cancer samples undergoing more or less of a FFA process in a way that is associated with distinct patient survival rates.