Downregulation of Wilms' tumor 1 protein inhibits breast cancer proliferation

Zapata‐Benavides, Pablo; Tuna, Musaffe; López-Berestein, Gabriel; Tari, Ana M.

doi:10.1016/s0006-291x(02)00751-9

Cited by 53 publications

(67 citation statements)

References 27 publications

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“…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. To directly address these conflicting data, we expressed different WT1 isoforms in a mammary epithelial cell line that lacks endogenous WT1 expression.…”

Section: Discussionmentioning

confidence: 68%

“…Using reverse transcription-polymerase chain reaction (RT-PCR), we were only able to detect WT1 expression in one of 20 samples of mammary epithelium, but we detected WT1 expression in 27 of 31 primary breast carcinoma specimens. Subsequently, Miyoshi et al (2002) reported a correlation between increased WT1 expression and poor long-term survival in women with breast cancer, and Zapata- Benavides et al (2002) reported a correlation between WT1 expression levels and the proliferative rates of breast cancer cell lines. Taken together, these data suggest that WT1 might function as a tumor-promoting gene in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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The role of WT1 (Wilm's tumor suppressor gene) in breast cancer is controversial, with evidence for both tumorpromoting and tumor-suppressing activities. In order to address this question, we expressed different WT1 isoforms in the mammary epithelial cell line H16N-2, which does not express endogenous WT1. Cells were stably transfected with either WT1 (ÀEx5/ÀKTS) or WT1 ( þ Ex5/ þ KTS) under the control of the inducible metallothionein promoter. Induction of WT1 (ÀEx5/ ÀKTS) upregulated p21, causing a slowing of proliferation and a G2-phase cell cycle arrest. In artificial basement membrane, the WT1 (ÀEx5/ÀKTS) isoform promoted the appearance of highly organized acinar cellular aggregates. In contrast, WT1 ( þ Ex5/ þ KTS) had no effect on p21 or proliferation, but rather caused an epithelial-mesenchymal transition and a redistribution of E-cadherin from the cell membrane to the cytoplasm. This isoform also causes the cellular aggregates growing in artificial basement membrane to appear significantly less organized than control cells. Thus, different WT1 isoforms have distinct effects in this cell line, suggesting that depending on the ratio of WT1 isoform expression in mammary epithelial cells, WT1 could function to either promote or suppress a transformed phenotype.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…[40][41][42] Different strategies have been used to decrease the WT1 production and, thereby, inhibit cancer cell proliferation, induce tumor apoptosis and sensitize tumor cells to chemotherapy and radiotherapy. [23][24][25][26][27][28][29][30][31] In previous studies, we showed that WT1 is expressed in B16F10 murine melanoma cell line and that in vitro RNAi silencing of WT1 expression results in the inhibition of cell proliferation, induction of apoptosis, caspase-3 activation and poly-(ADP-ribose)polymerase cleavage in vitro. 30 In this study, we extended this analysis to show that in vivo aerosol delivery of PEI-WT1-1 RNAi or PEI-WT1-2 RNAi complexes effectively reduces the metastatic tumor burden in the lungs of B16F10 mice.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25][26][27][28][29][30][31][32][33][34][35] WT1 encodes a transcription factor that is involved in gonadal development. Mutations in WT1 were initially found to cause urogenital disease and kidney tumors, suggesting that it is a tumor suppressor.…”

Section: Introductionmentioning

confidence: 99%

WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

et al. 2009

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The Wilms' tumor gene 1 (WT1) is a universal tumor antigen and consequently a good therapeutic target for the development of gene therapy strategies. Earlier, we reported the in vitro efficacy of WT1 RNAi in the inhibition of B16F10 murine melanoma cell line growth. In this study, we used an aerosol system to deliver WT1 RNAi complexes, polyethyleneimine (PEI)-WT1-1 or PEI-WT1-2, to the lungs of mice with B16F10 lung metastasis. This treatment produced a statistically significant (P ¼ 0.020) reduction in the number and size of lung tumor foci, resulting in decreased lung weight and tumor index in treated mice compared with controls. The WT1 RNAi treatment also reduced the number and size of tumor blood vessels, suggesting decreased angiogenesis. Furthermore, the treated lung tissue showed cells in the tumor infiltrations undergoing apoptosis and elevated expression of the proapoptotic genes Bcl-xS and Bax, suggesting an activation of the intrinsic apoptotic pathway. Overall, WT1-1 treatment prolonged the mean survival time of tumor-bearing mice in comparison with the control and WT1-2-treated mice. Our data show that WT1 gene silencing in vivo by aerosol delivery of PEI-WT1 RNAi complexes is an effective therapeutic strategy for the treatment of lung metastases.

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“…Approximately 10-15% of sporadic Wilms' tumours carry mutations in the WT1 gene, and also humans with germline mutations in WT1 have a predisposition to Wilms' tumours and developmental malformations of the urogential system (Rivera and Haber, 2005). Furthermore, high levels of wild-type WT1 protein can be found in a variety of human malignancies, for example, leukaemia (Bergmann et al, 1997), breast (Loeb et al, 2001), lung (Oji et al, 2004), colon (Oji et al, 2003) and skin cancer (Rodeck et al, 1994), and downregulation of WT1 has been shown to inhibit in vitro proliferation of leukaemia (Yamagami et al, 1996) and breast cancer cells (Zapata-Benavides et al, 2002).…”

mentioning

confidence: 99%

hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation

et al. 2006

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The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is mutated in Wilms' tumours and highly expressed in a wide variety of other malignancies. WT1 is a transcription factor that is likely to have additional, post-transcriptional, regulatory roles, although the molecular mechanisms by which WT1 acts remain poorly understood. We have combined genetic and biochemical approaches to show, that endogenous WT1 binds to heterogeneous nuclear ribonuclear protein U (hnRNP-U), that this interaction does not require any other proteins or nucleic acids, involves the zinc-fingers of WT1 and the middle domain of hnRNP-U, and that hnRNP-U can modulate WT1 transcriptional activation of a bona fide WT1 target gene. These findings increase our knowledge of how WT1 exerts its transcriptional regulatory role and suggests that hnRNP-U may be a candidate Wilms' tumour gene at 1q44.

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Downregulation of Wilms' tumor 1 protein inhibits breast cancer proliferation

Cited by 53 publications

References 27 publications

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

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

WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation

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