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Lack of Transforming Growth Factor-ß₁ Expression in Benign Skin Tumors of p53^null Mice Is Prognostic for a High Risk of Malignant Conversion¹

Department of Medical Genetics, University of Glasgow, Duncan Guthrie Institute, Yorkhill, Glasgow, G3 8SJ [W. C., E. D., R. J. A.], and the CRC Departments of Medical Oncology, University of Glasgow, CRC Beatson Laboratories, Alexander Stone Building, Garscube Estate, Bearsden, Glasgow G61 1BD [C. J. K., A. B.], United Kingdom

Expression of transforming growth factor ß1 (TGFß₁) protein was examined in chemically induced benign skin tumors with genetically defined empirical risks for malignant conversion. Benign tumors induced in mice which have both alleles of the p53 gene deleted have a malignant conversion frequency of 50%, whereas similar tumors induced in wild-type and heterozygous p53 mice have conversion probabilities of 3 and 8%, respectively (Kemp et al., Cell, 74: 813–822, 1993). The TGFß₁ antibody, anti-CC (1-30-1), was shown to stain either the proliferative keratinocyte compartment of the tumor or the tumor stroma, whereas another TGFß₁ antibody, anti-LC (1-30-1), stained highly differentiated granular cells of the tumors. A strong correlation was found between staining of the proliferative keratinocyte compartment of tumors with the anti-CC (1-30-1) antibody and tumor genotype. Only 18% (6 of 32) of homozygous p53 null tumors showed any basal keratinocyte staining with this antibody, whereas over 80% (32 of 38) of heterozygous and wild-type tumors showed positive staining. Additionally, in most tumors examined, the spatial distribution of staining for the proliferating cell nuclear antigen appeared to be mutually exclusive with that of TGFß₁ on adjacent serial sections. This suggests that, in these cases, tumor keratinocytes are sensitive to negative growth regulation by TGFß. TGFß₁ protein staining in benign tumors is thus prognostic for a low probability of malignant conversion, and its expression may be mechanistically involved in limiting malignant conversion since, at the benign tumor stage examined, keratinocytes are still sensitive to growth inhibition by TGFß₁.

¹ This work was supported by the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 3/30/94. Accepted 9/14/94.

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