p53-independent expression of p21waf1/cip1 in preinvasive and invasive squamous neoplasms of the uterine cervix.

Although mutations of the p53 gene are the most common genetic alteration in human tumors, they are relatively rare in cervical carcinomas, possibly because human papillomaviruses of the oncogenic type encode for an oncoprotein that leads to the ubiquitin-mediated destruction of p53. An important mediator of p53-induced cell-cycle arrest is p21waf1/cip1, and although several studies evaluated invasive and preinvasive cervical lesions for p53 expression, none has studied expression of this important downstream effector. We examined normal cervical squamous epithelium, squamous cell carcinomas, and a range of preinvasive cervical lesions for expression of p53, p21waf1/cip1, and the proliferation-associated antigen, Ki-67, by immunohistochemical analysis. p53 expression was absent in normal squamous epithelium and all dysplasias regardless of severity, consistent with the presence of predominantly wild-type p53. Invasive carcinomas were mostly negative but contained occasional small nests of cells immunoreactive for p53. p21waf1/cip1, on the other hand, was expressed in all normal squamous epithelium and all preinvasive and invasive lesions. In normal squamous epithelium, the basal and immediate parabasal layers were negative, with the early differentiating layers positive. Expression was increased in dysplasias compared with normal squamous epithelium, both in number of immunoreactive nuclei and intensity of staining. The highest expression was seen in high-grade dysplasias and invasive carcinomas. Ki-67 expression also increased with increasing severity of the lesion, but p21waf1/cip1 and Ki-67 seemed to be expressed in different cells, a fact that was confirmed by double immunohistochemical staining for these two proteins on the same sections. This paradoxical increase in p21waf1/cip1 expression and mutually exclusive expression might be related to the role of p21waf1/cip1 in differentiation.