Aberrant expression of p27(Kip1)-interacting cell-cycle regulatory proteins in ovarian clear cell carcinomas and their precursors with special consideration of two distinct multistage clear cell carcinogenetic pathways.
ABSTRACT We have previously reported that alterations of p27(Kip1)-interacting cell-cycle proteins frequently occur during the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA; Yamamoto et al., Histopathology in press, 20). However, CCA also occurs in association with clear cell adenofibroma (CCAF). In this study, the expressions of p27(Kip1)-interacting proteins, i.e., p27(Kip1), Skp2, Cks1, cyclin A, cyclin E, and the Ki-67 labeling index (LI), were analyzed in 25 CCAFs (11 benign and 14 borderline) and 15 CCAF-associated CCAs, and compared with the expression status of each protein in the 23 previously studied endometriosis-associated CCAs. Although aberrant expression of all p27(Kip1)-interacting proteins was more frequent in the CCAF-associated CCAs than in the benign CCAFs, statistical significance was found only for Cks1 overexpression. The frequencies of p27(Kip1) downregulation and overexpression of Skp2 and cyclin A were significantly lower in CCAF-associated than in endometriosis-associated CCAs (P < 0.05, respectively). The frequencies of p27(Kip1) downregulation and Skp2 overexpression in borderline CCAFs were significantly lower than those in atypical endometriosis components in endometriosis-associated CCAs (P < 0.05, respectively). Mean Ki-67 LI increased significantly through benign (4.9%) to borderline (11.1%) CCAF and to CCAF-associated CCA (30.6%), but the latter two values were significantly lower than those in atypical endometriosis (21.4%) and endometriosis-associated CCA (46.9%; P < 0.05, respectively). These data suggest that accumulated alterations of p27(Kip1)-interacting proteins may accelerate the development of CCAs regardless of their carcinogenetic pathways, but that tumor cells in the CCAF-associated pathway appear to show slower cell-cycle progression than those in the endometriosis-associated pathway, possibly accounting for the distinct clinicopathological features of the two CCA subtypes.
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ABSTRACT: The clinicopathologic features of 472 ovarian epithelial clear cell neoplasms (4 adenofibromas [AFs], 41 atypical proliferative [borderline] tumors [APTs], and 427 carcinomas [CAs]) were studied in order to elucidate the morphologic steps involved in the pathogenesis of these tumors and determine whether clear cell CA is a type I or type II tumor in the dualistic model of ovarian carcinogenesis. Thirty-three percent of the CAs had an adenofibromatous background [CA(AF+)], and 67% did not [CA(AF-)]. Endometriosis was found in all types of tumors, but tumors arising in endometriotic cysts were more frequent with CA(AF-)s (p<0.0001). The subset of women with CA(AF-)s with endometriosis were younger (p<0.0001), their tumors were more frequently cystic (p<0.0001), they more commonly had a mixed carcinoma component of non-clear cell type (p=0.006), and they were more frequently oxyphilic (p=0.015) compared with CA(AF+)s. The architecture of the former tumors was more commonly papillary compared to tubulocystic in the latter (p=0.0006). Atypical endometriosis was more common in CA(AF-)s than in AFs, APTs, and CC(AF+)s [p=0.004]. The subset of CA(AF-)s without endometriosis presented more frequently in advanced stage (>I) and were higher grade compared to CA(AF+)s or CA(AF-) with endometriosis (p-values, <0.0001 to 0.0071). All AFs and APTs were stage I compared to 79% of CA(AF+)s. An increase in mean tumor size correlated with each respective tumor category from AF (6.8 cm) to CA(AF+) [12.9 cm]. Notable nuclear atypia was absent in all AFs but was focally present in 27% of APTs and in the adenofibromatous background of 24% of the CA(AF+)s. An increase in the proportion of carcinoma in the CA(AF+)s correlated with an increase in grade and advanced stage. In summary, ovarian clear cell CA appears to develop along two pathways, both of which are related to endometriosis. We speculate that, in one, epithelial atypia arises in an endometriotic cyst and then evolves into clear cell CA, and, in the other, non-cystic endometriosis induces a fibromatous reaction resulting in the formation of AF, which then develops into APT and subsequently a clear cell CA. The absence of endometriosis or adenofibromatous components in CC(AF-)s may be due to overgrowth and obliteration by the invasive carcinoma. Finally, the findings in this study support the view that both types of clear cell CA [CC(AF+) and CC(AF-)] are more closely related to type I tumors.Journal of Cancer. 01/2011; 2:94-106.
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ABSTRACT: Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27(Kip1) by the ubiquitin proteasomal system (UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of Cks1 is that of an essential adaptor that regulates p27(Kip1) abundance by facilitating its interaction with the SCF-Skp2 E3 ligase which appends ubiquitin to p27(Kip1) and targets it for degradation through the UPS. In addition, emerging research has uncovered p27(Kip1)-independent roles of Cks1 which have provided crucial insights into how it may be involved in cancer progression. We review here the structural features of Cks1 and their functional implications, and also some recently identified Cks1 roles and their involvement in breast and other cancers.Journal of Cancer Therapy 10/2013; 4(8):1341-1354.
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ABSTRACT: CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) family that interacts with cyclin-dependent kinases and plays an important role in cell cycle progression. We and others have shown that CKS1B amplification located on chromosome 1q21 is an adverse prognostic factor in multiple myeloma, but its relationship with CKS1B nuclear protein expression, is unclear. The aim of this study was to correlate nuclear CKS1B protein immunoreactivity, 1q21 amplification status, p27(Kip1) expression and survival in patients with newly-diagnosed multiple myeloma. Nuclear expression of CKS1B and p27(Kip1) was evaluated by immunohistochemistry in decalcified, paraffin-embedded bone marrow biopsies from 94 patients with newly diagnosed multiple myeloma. Clonal plasma cells of the bone marrow aspirates from the same cohort were examined for CKS1B gene status by interphase cytoplasmic fluorescence in situ hybridization. Fluorescence in situ hybridization detected the 1q21 amplification in 36 (38%) of the 94 patients and immunohistochemistry showed CKS1B protein expression in 37 (39%). Thirty-two (86%) of the 36 amplified (1q21) cases expressed CKS1B and 31 (84%) of the 37 CKS1B immunore-active cases had amplified 1q21. 1q21 amplification and CKS1B protein expression were strongly correlated (P<0.0001). CKS1B protein expression was inversely correlated with p27(Kip1) immunostaining (P<0.0001) and was associated with a shorter overall survival (median 44.5 versus 89.3 months, P<0.0001). Immunohistochemistry for CKS1B is a simple, rapid method that appears to predict 1q21 amplification and adverse outcome for risk stratification of patients with multiple myeloma.Haematologica 09/2010; 95(9):1542-7. · 5.94 Impact Factor