ALTERED EXPRESSION OF THE WT1 WILMS-TUMOR SUPPRESSOR GENE IN HUMAN BREAST-CANCER

The product of the WT1 Wilms tumor suppressor gene controls the expres sion of genes encoding components of the insulin-like growth factor an d transforming growth factor beta signaling systems, The role of these growth factors in breast tumor growth led us to investigate possible WT1 gene expression in normal and cancerous breast tissue, WT1 was det ected by immunohistochemistry in the normal mammary duct and lobule, a nd the patterns of expression were consistent with developmental regul ation, In a survey of 21 infiltrating tumors, 40% lacked immunodetecta ble WT1 altogether and an additional 28% were primarily WT1-negative. Cytoplasmic, but not nuclear, localization of WT1 was noted in some tu mor cells and WT1 mas detected, sometimes at. high levels, in more-adv anced estrogen-receptor-negative tumors, In this highly malignant subs et, the tumor suppressor protein p53, which can physically interact wi th WT1, was also sometimes detected, WT1 mRNA was detected in normal a nd tumor tissue bg reverse transcription-coupled PCR, Alternative spli cing of the WT1 mRNA may regulate gene targeting of the WT1 protein th rough changes either in its regulatory or zinc-finger domains, The rel ative proportions of WT1 mRNA splice variants were altered in a random sample of breast tamers, providing evidence that different tumors mag share a common WT1-related defect resulting in altered regulation of target genes.