High levels of expression of p27(KIP1) and cyclin E in invasive primary malignant melanomas

Cancer cells have abnormal cell cycle regulation which favors accelerated p roliferation, chromosomal instability, and resistance to the senescence res ponse. Although the p16(INK5n) locus is the most prominent susceptibility l ocus for familial melanomas, the low frequency of p16 mutations in sporadic melanomas suggests additional alterations in other cell cycle regulatory g enes. Here we used primary melanoma tumors to reveal early cell cycle alter ations that could be masked in advanced metastatic lesions due to their inh erently high genetic instability. Unexpectedly, the cyclin-dependent kinase inhibitors p27(KIP1) and/or p21(Waf-1/SDI-1) were found to be expressed in 13 of 18 (72%) of the primary melanomas with a Breslow thickness greater t han 0.076 mm, In general, p27 and/or p21 staining in the primary tumors cor related with low Ki-67 index, Importantly, most of the p21- and p27-positiv e tumors expressed high levels of cyclin D1 and cyclin E, In proliferating cells p27 is predominantly associated with cyclin D-CDK4 complexes, but doe s not inhibit the kinase activity, whereas in quiescent cells p27 is found associated with inactive CDK2 complexes, p27 was also expressed at high lev els in proliferating primary melanomas in culture, and found to be associat ed with active cyclin E-CDK2 complexes containing high levels of cyclin E, It is thus Likely that accumulation of cyclin E overcomes the potent inhibi tory activity of p27 and p21 in CDK2 complexes. Of the primary melanomas wi th no indication of invasiveness, only three of 15 (20%) were positive for p27 and/or p21, We propose that high levels of p27 and p21 may confer upon melanoma tumors their characteristic resistance to conventional therapies. In turn, high levels of cyclins E and D1 may contribute to unlimited prolif eration in primary melanomas that express the tumor suppressor p16(INK4).