Untersuchungen zur Expression von High-Mobility-Group-Genen und -Proteinen unter besonderer Berücksichtigung des Mammakarzinoms

Abstract

The aim of this thesis was to investigate the expression pattern of the high mobility group genes/proteins HMGA1 and HMGB1 by molecular biological methods mainly focussing on human primary breast cancer. HMGA1 expression analyses by immunohistochemistry in a series of 170 primary breast cancer samples showed a strong variation of HMGA1 expression among the tumours. Based on an immunoreactive score (IRS) 14.1% of the tumour samples were scored to IRS 8-12 (strong positivity for HMGA1), 24.7% were scored to IRS 4-6 (moderate positivity), 25.3% were scored to IRS 1-3 (weak positivity), and 35.9% showed no positivity at all. Statistical analyses revealed a strong positive correlation between tumour grade and HMGA1 expression. The HMGA1 expression level can be considered as a potential prognostic marker for breast cancer. Cell culture experiments have shown that MCF-7 breast cancer cells are capable of assimilating HMGA1b protein and are furthermore able to transport the protein into their nuclei. Elevated amounts of HMGA1b protein in MCF-7 cells lead to an overexpression of the platelet-derived growth factor A gene. The mitogenic effect of PDGFA may also contribute in vivo to the malignant phenotype of breast cancer cells. It turned out that the processed HMGB1 related sequence HMG1L3 could be activated as a terminal exon of a splice variant of the SP100 gene. SP100-HMG represents the first example of exonisation of a processed pseudogene and provides a model showing how new functional exons can arise. An expression analysis of the HMGB1 gene in a subset of 13 primary breast cancer samples revealed a strong intertumoural variation in the 1.4 and 2.4 kb transcript. This variation may contribute to the different response of breast tumours to endocrine therapy but it is almost certain to affect the steroid hormone dependent growth of breast cancer cells.