The motility of breast cancer cells is stimulated by HMGB1/RAGE interaction but the truncated form lacking the C terminus has no effect

HMGB1/RAGE is identified as a ligand-receptor pair that plays an important role in tumorogenesis. HMGB1 and RAGE levels are higher in most human tumors and their overexpression is associated with tumor progression. The causes of breast cancer are still poorly understood. One reason might be the existence of subtypes within various cellular mechanisms as hormone-dependent and hormone -independent malignant processes. We investigated the effect of HMGB1 protein and its truncated form lacking the C terminus on the RAGE expression and cell motility of breast cancer cell lines; MCF7-noninvasive, MDA-MB-231-invasive and normal breast epithelial one MCF10. The results demonstrate that the effects of HMGB1 and HMGB1∆C through RAGE association are observed exclusively for the hormone independent MDA-MB-231 cell line. The mobility of MDA-MB-231 cells was stimulated only by the full length HMGB1. Our results suggest that HMGB1/RAGE signaling should be considered as an essential process for the development of hormone independent breast cancers with great invasive potential. The truncated form plays the role of a blocking molecule that ”locks” the receptor and inactivates it. This makes the tailless molecule a promising therapeutic agent that competes for the biologically active HMGB1 ligand and prevents the downstream signaling through RAGE

High mobility group box 1 protein (HMGB1) stimulates the nuclear accumulation of p53

p53 is usually regarded as a tumour suppressor protein but its constant activation may result in pro-tumorigenic inflammation. The activation of p53 can be provoked by an increase in its concentration as a result of high level transcription, by transformation of the p53 protein to an active conformation or by its translocation from the cytoplasm to the nucleus. p53 can be activated by a wide variety of stress signals that a cell might encounter during malignant progression, such as genotoxic damage, oncogene activation and hypoxia. We found that the HMGB1 protein can play the role of a signal molecule that provokes the accumulation of p53 in the nucleus. Only the full-length protein stimulated the translocation of p53 from the cytosol to the nucleus and the effect was considerably strong and almost equal to that generated by the positive control actinomycin D. The truncated tail less form of HMGB1 was not functional. This supported the hypothesis that the C terminus plays an important role in regulating the properties of HMGB1