Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer

Abstract

The product of the WT1 Wilms tumor suppressor gene controls the expression of genes encoding components of the insulin-like growth factor and transforming growth factor ␤ 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 detected by immunohistochemistry in the normal mammary duct and lobule, and the patterns of expression were consistent with developmental regulation. In a survey of 21 infiltrating tumors, 40% lacked immunodetectable WT1 altogether and an additional 28% were primarily WT1-negative. Cytoplasmic, but not nuclear, localization of WT1 was noted in some tumor cells and WT1 was detected, sometimes at high levels, in more-advanced estrogenreceptor-negative tumors. In this highly malignant subset, the tumor suppressor protein p53, which can physically interact with WT1, was also sometimes detected. WT1 mRNA was detected in normal and tumor tissue by reverse transcription-coupled PCR. Alternative splicing of the WT1 mRNA may regulate gene targeting of the WT1 protein through changes either in its regulatory or zinc-finger domains. The relative proportions of WT1 mRNA splice variants were altered in a random sample of breast tumors, providing evidence that different tumors may share a common WT1-related defect resulting in altered regulation of target genes.

Isoforms of Wilms’ tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells

“…Silberstein et al (1997) reported loss of WT1 expression in breast tumors, and Zhang et al (2003) reported observations consistent with a tumor suppressor role. In contrast, our group reported overexpression of WT1 in breast tumors as compared with normal mammary epithelium (Loeb et al, 2001), and Zapata- Benavides et al (2002) reported data consistent with an oncogenic role.…”

“…We investigated the function of individual WT1 isoforms expressed in isolation, but primary breast tumors frequently express multiple isoforms (Silberstein et al, 1997;Loeb et al, 2001). Thus, the net effect of WT1 will probably reflect a balance of the effects of different isoforms.…”

“…Variable expression of WT1 isoforms in breast tumors has been reported (Silberstein et al, 1997;Loeb et al, 2001). We, therefore, hypothesized that different WT1 isoforms might have different effects on mammary epithelial cells, thus accounting for the conflicting reports of the role of this gene in the development of breast cancer.…”

“…Silberstein et al (1997) reported that WT1 is expressed in mammary epithelial cells, with higher levels of expression in myoepithelium than in luminal epithelium. They also reported a loss of WT1 expression in most breast tumors, and they observed a correlation between loss of WT1 expression and expression of the estrogen receptor (ER).…”

Immunohistochemical detection of WT1 protein in a variety of cancer cells

“…However, immunohistochemical data on WT1 expression in other types of cancers are either lacking or conflicting. 17,18,[21][22][23][24] As for staining patterns, cytoplasmic staining has been regarded as nonspecific and not been counted as positive in most previous reports. Therefore, the cytoplasmic staining of WT1 had not been evaluated in most types of tumors until now.…”