Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells

Numerous studies have demonstrated that overexpression or aberrant expressi on of the HMGI(Y) family of architectural transcription factors is frequent ly associated with both neoplastic transformation of cells and metastatic t umor progression. Little is known, however, about the molecular roles playe d by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acqui re the ability to form both primary and metastatic rumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rathe r than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furth ermore, expression of either antisense or dominant-negative HMGI(Y) constru cts inhibits both the rate of proliferation of tumor cells and their abilit y to grow anchorage independently in soft agar. Array analysis of transcrip tion profiles demonstrates that the HMG-I and HMG-Y isoform proteins each m odulate the expression of distinctive constellations of genes known to be i nvolved in signal transduction, cell proliferation, tumor initiation, invas ion, migration, induction of angiogenesis, and colonization. immunohistoche mical analyses of tumors formed in node mice indicate that many have underg one an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic tra nsformation and metastatic progression and suggest that induction of integr ins and their signaling pathways may play significant molecular roles in th ese biological events.