Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

Abstract

Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone 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 transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events.

ACKNOWLEDGMENTS

This work was supported by NIH grant RO1-GM46352 (to R.R.) and U.S. Army Breast Cancer Research Grant DAMD17-96-16249 (to Y.L.).

We sincerely thank M. Nissen and other members of both the Reeves laboratory and that of M. Griswold (Washington State University) for helpful discussions and technical assistance during the course of this work. Our thanks also go to Charles W. Leathers (Washington State University College of Veterinary Medicine) for assistance with histological analyses, Adrea Cupp (Center for Reproductive Biology, Washington State University) for advice on immunohistochemical staining, and Eric Nilsson (also of the Center for Reproductive Biology, Washington State University) for assistance with tumor dissections.

ADDENDUM

It has recently been reported (131) that Rat-1a fibroblast cells overexpressing either the HMG-I, HMG-Y, or HMGI-C protein form tumors and distant metastases when injected into nude mice.