Low‐molecular weight forms of cyclin E differentiate ovarian carcinoma from cells of mesothelial origin and are associated with poor survival in ovarian carcinoma

Abstract

BACKGROUND. The authors recently reported on the role of cyclin E in differentiating ovarian/primary peritoneal carcinoma from malignant peritoneal mesothelioma using gene expression arrays. In the current study, they analyzed the expression of low‐molecular weight (LMW) forms of cyclin E in ovarian carcinoma, malignant mesothelioma, and benign reactive effusions. METHODS. Cyclin E protein expression was analyzed in 98 effusions (72 ovarian carcinomas, 14 malignant mesotheliomas, and 12 reactive specimens) using immunoblotting. Sixty‐two ovarian carcinoma effusions were studied further for cyclin E expression using immunohistochemistry. The correlations between cyclin E expression in ovarian carcinoma and clinical parameters, including chemotherapy response, were analyzed. RESULTS. LMW forms of cyclin E were identified in 54 of 72 ovarian carcinoma effusions (75%) compared with 1 of 14 malignant mesothelioma effusions (7%) and 1 of 12 reactive effusions (8%) (P < .001). Their presence in ovarian carcinoma was associated with a higher percentage of cyclin E‐positive cells (P = .001) and increased staining intensity (P < .001) using immunohistochemistry. The presence of LMW forms of cyclin E was correlated with shorter overall survival (P = .021) and progression‐free survival (P = .020). The presence of a higher percentage of cyclin E‐positive cells using immunohistochemistry was correlated with shorter progression‐free survival (P = .026). No association with chemotherapy response was observed. CONCLUSIONS. LMW forms of cyclin E differentiated ovarian carcinoma from benign and malignant mesothelial cells and were associated with increased protein expression using immunohistochemistry. The expression of LMW cyclin E forms was not associated with chemotherapy response, although it may be a marker of aggressive disease in patients with metastatic ovarian carcinoma. Cancer 2007. © 2007 American Cancer Society.

Cytoplasmic Cyclin E and Phospho–Cyclin-Dependent Kinase 2 Are Biomarkers of Aggressive Breast Cancer

“…13e16 The significance of LMW-E, which was originally discovered in breast cancer by our group and subsequently by others, 17e20 has recently been the subject of several review articles. 21e23 These isoforms are also found in ovarian cancer, 4,24 melanomas, 2 gastric cancer, 25 colorectal cancer, 26e28 lung cancer, 29 and renal cell carcinomas 30 and are strongly associated with poor survival in patients. 4,26,31 Work from our laboratory has implicated LMW-E in breast cancer oncogenesis.…”

“…21e23 These isoforms are also found in ovarian cancer, 4,24 melanomas, 2 gastric cancer, 25 colorectal cancer, 26e28 lung cancer, 29 and renal cell carcinomas 30 and are strongly associated with poor survival in patients. 4,26,31 Work from our laboratory has implicated LMW-E in breast cancer oncogenesis. For example, LMW-E i) is biochemically hyperactive because of its increased affinity for cdk2 and resistance to inhibition by the CDK inhibitors p21 and p27 32 ; ii) is resistant to the growth-inhibiting effects of antiestrogens 33 and aromatase inhibitors 34 ; iii) promotes deregulation of cell cycle, 35 centrosome amplification, 13 and genomic instability 33 ; iv) causes premature inactivation of Cdc25C and PLK1, leading to faster mitotic exit 16 ; v) is sufficient to render human mammary epithelial cells tumorigenic and leads to altered acinar morphogenesis 36 ; vi) phosphorylates Hbo1 to mediate a cancer stem cell-like environment 14 ; and vii) is a downstream oncogenic target of protein kinase Ci.…”

Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells

“…However, in addition to the full length cyclin E, a series of low-molecular-weight isoforms (LMW-Es) is uniquely present in some cancers such as breast, colon, ovarian and hematological malignancies (Scuderi et al, 1996;Wang et al, 1996;Harwell et al, 2000;Davidson et al, 2007). Having the mass from 45 to 33kDa, these LMW forms are generated in a tumor-specific post translational cleavage which is distinct from proteasome mediated degradation of cyclinE.…”

18th International Congress of Cytology Paris, France, May 26-30, 2013

“…4,5 However, metastatic carcinomas to the lung should always be considered when psammoma bodies are microscopically observed. In our case immunochemistry and radiographic scanning helped us establish the diagnosis of papillary lung adenocarcinoma with psammoma bodies.…”

“…Our group previously applied gene expression array technology to the diagnosis of malignant effusions, identifying novel markers differentiating between serous ovarian/peritoneal carcinoma (OC/PPC) and malignant mesothelioma (MM) [1], between serous OC/PPC and breast carcinoma (BC) [2], and between breast and lung adenocarcinoma [3]. Validation of the two first studies in follow-up studies using IHC, flow cytometry (FCM) and quantitative PCR (qPCR) identified several promising markers differentiating these tumors at the mRNA and protein level, including the FOLR1, FOLR3, RAB25, PRAME, EHF and SCARA3 mRNA as markers of OC/PPC, TNXB as MM marker and AZGP1 and SPDEF mRNA as markers of breast carcinoma, as well as claudins, MUC4, Tenascin-X and Folate receptor-α (FRα) as discriminators at the protein level [4][5][6][7][8][9][10][11][12][13][14][15]. Study by another group recently showed good performance of the Tissue of Origin Test array, performed on mRNA from cell blocks, in diagnosing the origin of tumors detected in effusions [16].…”