P21(WAF1 CIP1) IS ASSOCIATED WITH CYCLIN D1(CCND1) EXPRESSION AND TUBULAR DIFFERENTIATION BUT IS INDEPENDENT OF P53 OVEREXPRESSION IN HUMANBREAST-CARCINOMA/

p21(WAF1/Cip1) is an inhibitor of cdk/cyclin complexes, and thus regul ates the cell cycle. p21 is also related to cell differentiation and i s regulated by wild-type p53, although p53-independent regulatory path ways have been proposed. In order to analyse p21 expression as well as its relationship with p53 in human breast cancer, an immunohistochemi cal analysis was undertaken of 77 breast carcinomas, 16 of them with a n in situ component; 30 adjacent normal tissue samples; and five non-n eoplastic specimens. Forty-four infiltrating carcinomas (57 per cent) were p21-positive. Expression of p21 was also observed in pre-invasive lesions, whereas normal ducts were negative or focally and weakly pos itive. p21 expression was associated with high histological grade (IIIII) (P=0.017) and poor tubule formation (P=0.002), and was significan tly less frequent in lobular carcinomas (P=0.0001). p21 positivity als o correlated with increased proliferation, but this seemed to be depen dent on the histological grade. Twenty carcinomas (26 per cent) showed p53 overexpression, but this was not associated with p21 negativity, suggesting the existence of p53-independent mechanisms for p21 regulat ion in vivo. Cyclin D1(CCND1) expression was analysed in the same seri es and an association between p21 and cyclin D1 expression was found, since 23 of 26 cyclin D1-positive carcinomas were p21-positive (P<0.00 1 ...). In conclusion, p21 is frequently overexpressed in breast carci nomas and this occurs in the early stages of neoplastic progression. T his overexpression seems to be independent of p53 status and might be involved in cyclin D1 modulation. (C) 1998 John Wiley & Sons, Ltd.