ELEVATED HIGH-MOBILITY GROUP-I(Y) GENE-EXPRESSION IS ASSOCIATED WITH PROGRESSIVE TRANSFORMATION OF MOUSE MAMMARY EPITHELIAL-CELLS

The high mobility group (HMG) proteins I and Y are well characterized nonhistone chromosomal proteins which bind to A . T-rich regions of DNA, and may regulate gene expression and/or DNA replication. We utilized a series of mouse mammary epithelial preneoplastic and tumor cell lines to explore the relationship between neoplastic transformation and HMG-I(Y) gene expression. The cell lines used in this study were originally derived from a single hyperplastic outgrowth, and exhibit a distinct gradient of preneoplastic to highly metastatic transformation states. We measured the levels of HMG-I(Y) gene expression in these cell lines during the different phases of cell growth in culture. At both subconfluent and confluent cell densities, elevated levels of HMG-I(Y) mRNA were directly correlated with the relative degree of neoplastic transformation and metastatic progression of these cells. HMG-I(Y) mRNA levels were always highest in proliferating cells. However. the differences in HMG-I(Y) gene expression between the cell lines were greatest at confluent cell density, when the cells were not actively proliferating. HMG-I(Y) mRNA was detectable in normal primary mouse mammary epithelium proliferating in culture. However, the amount was much less than that measured in the cell lines, indicating that elevated HMG-I(Y) gene expression was also directly correlated with the conversion of normal mammary epithelium to the preneoplastic immortalized state. Southern blot analysis showed that alterations in HMG-I(Y) loci are also associated with the preneoplastic to neoplastic conversion of these cell lines, and this change may involve a gene conversion event between two different HMG-I(Y) loci. These results indicate that there is a strong correlation between elevated HMG-I(Y) gene expression and the progressive transformation of mouse mammary epithelial cells.