Association of p27Kip1, cyclin E and c-myc expression with progression and prognosis in HPV-positive cervical neoplasms

Recent studies demonstrated that a variety of human cancer cell lines express relatively high levels of p27Kip1 and that this might be associated with increased expression of Cyclin E. There is a feedback inhibitory loop between Cyclin E and p27Kip1, which can be counteracted by elevated c-myc activation. This study analyzed by immunohistochemistry the expression of p27Kip1, Cyclin E and c-myc in a series of HPV-positive cervical tissue samples representing various stages of cervical carcinogenesis, using 13 samples of normal epithelium, 24 low-grade CIN, 63 high-grade CIN, and 69 samples of invasive squamous cell carcinoma. To evaluate the cell proliferation, the Ki-67 Labelling Index (LI) was assessed. The presence of HPV was investigated by in situ DNA hybridization. We did not find any correlation between p27Kip1 expression and Ki-67 LI in normal and tumor tissue samples. There was evidence for an increase of p27Kip1 levels from low-grade to high-grade CIN. Cyclin E, c-myc and the Ki-67 LI were significantly increased during cervical carcinogenesis. Cyclin E and c-myc were positively correlated to cell proliferation in pre-cancerous lesions, but not related to overall survival in invasive carcinomas. Contrary to that, high levels of p27Kip1 are associated with poor overall survival in invasive cervical carcinomas of clinical stage IB. This may reflect the counteracting function of c-myc in blocking p27Kip1, thus representing the worst condition of a disturbed tumor cell cycle in cervical carcinoma, ultimately induced by HPV.