TRANSACTIVATION THROUGH ETS AND AP1 TRANSCRIPTION SITES DETERMINES THE EXPRESSION OF THE TUMOR-SUPPRESSING GENE MASPIN

Tumor invasion and metastasis are processes poorly understood at the m olecular level. Maspin is a serine protease inhibitor (serpin) with tu mor-suppressing function in the mammary gland. Maspin gene expression is decreased with malignancy and is lost in metastatic cells. We show in this report that differential expression of maspin in normal and ca rcinoma-derived mammary epithelial cells is regulated at the transcrip tional level, We have identified the Ets and Ap1 sites in the maspin p romoter that are active in regulating maspin expression in normal mamm ary epithelial cells but inactive in tumor cells, The Ets site alone i s sufficient to activate transcription in a heterologous promoter, whe reas the Ap1 site cooperates with Ets in activation. The enhancing fun ction by Ets and Ap1 elements is decreased in primary tumor cells (21N T) and is abolished in invasive tumor cells (MDA-231). Thus, loss of m aspin expression during tumor progression results at least in part fro m the absence of transactivation through the Ets and Ap1 sites.