[HTML][HTML] Loss of TGF-β or Wnt5a results in an increase in Wnt/β-catenin activity and redirects mammary tumour phenotype
K Roarty, SE Baxley, MR Crowley, AR Frost… - Breast Cancer …, 2009 - Springer
Introduction The tumour-suppressive effects of transforming growth factor-beta (TGF-β) are
well documented; however, the mechanistic basis of these effects is not fully understood.
Previously, we showed that a non-canonical member of the Wingless-related protein family,
Wnt5a, is required for TGF-β-mediated effects on mammary development. Several lines of
evidence support the hypothesis that Wnt5a acts as a tumour suppressor. In addition, it has
been shown that Wnt5a can antagonise canonical Wnt/β-catenin signalling in various cell …
well documented; however, the mechanistic basis of these effects is not fully understood.
Previously, we showed that a non-canonical member of the Wingless-related protein family,
Wnt5a, is required for TGF-β-mediated effects on mammary development. Several lines of
evidence support the hypothesis that Wnt5a acts as a tumour suppressor. In addition, it has
been shown that Wnt5a can antagonise canonical Wnt/β-catenin signalling in various cell …
Introduction
The tumour-suppressive effects of transforming growth factor-beta (TGF-β) are well documented; however, the mechanistic basis of these effects is not fully understood. Previously, we showed that a non-canonical member of the Wingless-related protein family, Wnt5a, is required for TGF-β-mediated effects on mammary development. Several lines of evidence support the hypothesis that Wnt5a acts as a tumour suppressor. In addition, it has been shown that Wnt5a can antagonise canonical Wnt/β-catenin signalling in various cell types. Here we test the hypothesis that TGF-β and Wnt5a can antagonise Wnt/β-catenin signalling and redirect mammary tumour phenotype. The results provide a new mechanism for the tumour-suppressive effects of TGF-β.
Methods
Wnt/β-catenin signalling was measured in tumours with altered TGF-β (dominant-negative TGF-β type II receptor, DNIIR) or Wnt5a (Wnt5a-/-) signalling as the accumulation of nuclear β-catenin using both confocal microscopy and cell fractionation. RT-PCR was used to measure the expression of Wnt/β-catenin target genes. Sca1 expression was determined by western blot and keratin (K) 6- and K14-positive populations were determined by immunohistochemistry.
Results
Loss of TGF-β or Wnt5a signalling resulted in stabilisation of nuclear β-catenin and expression of Wnt/β-catenin target genes suggesting that TGF-β and Wnt5a act to inhibit Wnt/β-catenin signalling in mammary epithelium. Increased expression of Sca-1 was observed in developing DNIIR and Wnt5a-/- mammary glands. DNIIR and Wnt5a-/- tumours demonstrated an expanded population of K6- and K14-expressing cells typically seen in Wnt/β-catenin-induced tumours.
Conclusions
The key findings here are that: TGF-β and Wnt5a regulate Wnt/β-catenin activity; and loss of TGF-β and Wnt5a redirect the phenotype of tumours so that they resemble tumours induced by activation of Wnt/β-catenin. The findings suggest a new mechanism for the tumour-suppressive effects of TGF-β.
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