Transcription Factors in Inflammation and Cancer

In the last few years it became increasingly evident that inflammatory processes are involved in cancer development. The transcription factor NF-kappa B has a crucial role in this context, as it can be activated by a great variety of inflammatory stimuli leading to the expression of regulators of the immune defense as well as survival genes. An activation of this transcription factor in combination with oncogenes such as c-Myc can lead to malignant transformation of cells or can trigger other pathological reactions. It is general assumed that synergistic cooperativity of several factors is pivotal for cancerogenesis. The aim of our project is to elucidate a potential cooperativity between the transcription factors NF-kappa B, c-Myc, androgen receptor and ERG. Preliminary experiments of our group could show correlations of these factors in prostate cancer. Furthermore, we could prove that some of them interact physically and that they influence each other functionally. The proposed project will investigate these molecular interactions in more detail and on two major levels: on one hand in prostate cancer and on the other hand by mathematical methods of systems biology. To that end, we will analyze the binding of transcription factors to cognate DNA elements; we will determine cooperative regulations of target genes; we will assess mutual transcriptional regulations of the transcription factors themselves and their upstream signaling pathways and we will finally investigate the feedback mechanisms that lead to a new steady state after a perturbation of the signaling network. Since two PhD students of our group are already funded by scholarships, the budget of the project can be used efficiently for building up a productive project team.

Our project (Transcription factors in inflammation and cancer) aimed to elucidate interactions between inflammatory processes and cancer development with an emphasis on prostate cancer. It is known for this type of cancer, that several transcription factors play a role. These are factors that bind to DNA and regulate the reading of the information that is stored in the DNA. One of these factors is androgen-receptor, which is activated by testosterone; another one is the oncogene MYC, a cancer-inducing factor, which increases cell division and which is frequently elevated in prostate cancer. Just a few years ago, an additional factor has been discovered, termed ERG, which was shown to be present in about 50% of prostate cancers. This gene becomes testosterone-inducible due to a DNA-damage and an erroneous repair leading to the synthesis of the corresponding protein in prostate glands, where it is normally not expressed. In addition to these as well as other molecular factors, inflammatory processes play a role in the development of various cancers including prostate cancer. These processes activate the transcription factor NF-kappa B, a key molecule in the stress response of the organism. NF-kappa B activates cellular survival mechanisms, which can have the consequence that transformed malignant cells survive and divide, which would otherwise die. While it is known for quite a while that the above mentioned molecular factors are involved in the development of prostate cancer, little is known about a potential cooperativity between them. In our study, we put a focus on the analysis of this cooperativity and we could gain interesting novel insights in the interplay of the various factors. We could show that androgen receptor, MYC, ERG and NF-kappa B are part of a complex regulatory circuit, influencing each other mutually. Moreover, we could prove direct physical interactions between them, which had been uncovered so far. Furthermore, we observed that ERG can bind directly to NF-kappa B binding sites on the DNA and that it can have enhancing or inhibitory effects on NF-kappa B activity depending on the specific fine structure of the DNA. The results of our study imply that the investigated factors have more than an additive effect and rather act in a cooperative manner finally promoting pathological self-enhancing feedback mechanisms. This hypothesis is also supported by mathematical models of the dynamic network. These models predict that a combined inhibition of androgen receptor and NF-kappa B should have a cooperative effect leading to the breakdown of the pathological signaling-network. This has an important implication for the therapy of metastasizing prostate cancer, suggesting that the currently applied chemical blockade of the androgen receptor might be combined with pharmaceutical inhibition of NF-kappa B in order to achieve a synergistic therapeutical effect.