Deregulation of Cyclin E2 expression and associated kinase activity in primary breast tumors

Abstract

The increased expression of G 1 cyclins has been associated with the many types of human tumors. In primary solid tumors however, the expression and activity of cyclin E2, the newest member of the G 1 cyclin family, is largely unknown. In this study we have analysed the expression of the E-type cyclins in primary solid tumors from breast, lung, uterus, ovary, colon, and rectal tissues. Relative gene expression was analysed by quantitative real-time reverse transcription polymerase chain reaction (Taqman). The levels of cyclin E1 and cyclin E2 were significantly elevated (23 vs 38%, respectively) in primary breast tumor samples relative to normal breast tissue controls. We also observed an inverse correlation between the expression of cyclin E1/ E2 and estrogen receptor in breast tumors. Our results demonstrate that the expression and associated catalytic activity for both cyclin E1 and cyclin E2 is elevated in primary breast tumors when compared to normal breast tissue. The increased level of cyclin E2 in breast tumors suggests that, similar to cyclin E1, it may contribute to the pathogenesis of breast cancer. Oncogene (2002) 21, 8529 -8534. doi:10.1038/sj.onc. 1206035Keywords: Cyclin E2; Cyclin E1; Cdk2; breast tumor Results and DiscussionA number of studies have demonstrated a strong correlation between elevated levels of cyclin E1 and tumor progression and mortality (Muller-Tidow et al., 2001;Geng et al., 2001;Keyomarsi et al., 1994; GrayBablin et al., 1996;Loden et al., 1999;Nielson et al., 1996;Porter et al., 1997;Bortner and Rosenberg, 1997). In addition, there is a correlation between elevated cyclin E1-Cdk2 kinase activity, increased phosphorylation of Rb, and increased rates of tumor cell proliferation in breast cancers (Loden et al., 1999). However, the expression and activity of cyclin E2 in solid tumors is largely unknown. Our initial characterization of cyclin E2 expression in tumor derived cell lines and primary mouse embryonic fibroblasts lacking Rb demonstrated a strong association between elevated levels of cyclin E2 and the functional inactivation of Rb (Gudas et al., 1999;Geng et al., 2001). We also demonstrated that cyclin E2 expression was elevated in lung tumor-derived cell lines in comparison to cell lines derived from normal lung tissue. Two recent studies evaluated the expression of cyclin E2 in early stage primary Non-Small Cell Lung Carcinoma (NSCLC) and in primary breast carcinoma (Muller-Tidow et al., 2001;Geng et al., 2001). Interestingly, no significant elevation of cyclin E2 transcript levels was found in any of the lung tumors. In contrast, increased expression of cyclin E2 was observed in 25% of primary breast carcinomas.To confirm and extend these recent observations we have analysed the expression of cyclin E2 in a variety of primary tumors and determined the catalytic activity associated with both cyclin E2 and cyclin E1 in primary breast tumors. Quantitative real-time RT -PCR (Taqman) analysis of primary tumor RNAs was used to determine the Relative Gene Expression (RGE) val...

Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer

“…Remarkably, although similar methods were used in both these papers (Nielsen et al, 1996;Keyomarsi et al, 2002), Nielsen et al (1996) reported very low to undetectable levels in normal breast tissue. On the other hand, quantitative RT-PCR also indicated that 23% of tumors overexpress cyclin-E compared to normal tissue (Payton et al, 2002). These results also confirm the strong relation between mRNA and protein cyclin-E levels in tumor tissue.…”

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