Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer

Abstract

Cyclin E is one of the key regulators of the G(1)/S transition in the cell cycle. Overexpression of cyclin E has been observed in several malignancies and is associated with high proliferation, aberrant expression of other cell cycle regulators and chromosomal instability in vitro. To explore potential associations between cyclin E deregulation and inactivation of the p53 tumor suppressor gene in human breast cancer, we investigated the immunohistochemical expression of cyclin E in paraffin embedded breast cancers from 270 women with known p53 status by cDNA based sequencing of the p53 gene. The breast cancers were divided into three subgroups according to the percentage of cyclin E-positive cells. One hundred and seventy-one patients (63%) had low cyclin E, 72 (27%) medium and 27 (10%) had high cyclin E content. Fifty-six percent (15/27) of the breast cancers with high cyclin E had p53 gene mutations, compared with 14% (24/171) of those with low cyclin E content (P < 0.0001). In p53 mutated breast cancers high cyclin E content was associated with insertions, deletions and nonsense point mutations in the p53 tumor suppressor gene, whereas low cyclin E was linked to p53 missense point mutations. We also observed statistically significant associations between a high cyclin E content and aneuploidy, high S phase, larger tumor size, estrogen receptor negativity, presence of axillary node metastases and high tumor grade. High cyclin E content was associated with poor overall survival in univariate and multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.3-4.5). In summary, our findings demonstrate that overexpression of cyclin E is associated with an aggressive tumor phenotype and specific types of p53 mutations.

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

“…The high frequency of p53 inactivation in our study together with that seen with other examples of mammary tumorigenic synergy -for example, p53 þ /À BRCA2 À/À mice (Jonkers et al, 2001) and in a p53 þ /À conditional Rb-inactivated mouse (Simin et al, 2004) support the notion that inactivation of p53, rather than haploinsufficiency, is a key event in mammary tumorigenesis in mice although a systematic study in spontaneous mammary lesions of mice is needed. This is supported by work on human breast cancers reporting that overexpression of cyclin E is associated with specific mutation types in p53 (Lindahl et al, 2004). It seems likely, therefore, that the increased tumorigenesis in our mice may be accounted for by increased p53 LOH (or loss of function) induced by cyclin E deregulation, and is consistent with our original hypothesis that deregulated cyclin E induces tumorigenesis through genomic instability.…”

Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer

“…Most studies evaluating the association of cyclin E with histopathological markers have found correlation with aggressive features such as high grade and negative hormone receptor status [17,19,27], and some studies furthermore a correlation with high Ki67 expression, younger age at diagnosis and large tumour size [22,23,43]. The associations in our study were similar; high cyclin E correlated with high grade, high Ki67 expression and cyclin A expression, ER and PR negativity, large tumour size and younger age at disease onset.…”

“…After estrogen treatment the cyclin E-CDK2 complex is activated by induction of cyclin D1-CDK4/6. High cyclin E expression causes chromosomal instability [18] and is often associated with aggressive disease features such as hormone receptor negativity, high grade and large tumour size in breast cancer [17,[19][20][21][22][23]. High cyclin E expression and particularly its low molecular weight (LMW) derivates have in most studies been an adverse prognostic factor [17,19,[20][21][22][23][24][25][26].…”

Retinoic acid mediates degradation of IRS-1 by the ubiquitin–proteasome pathway, via a PKC-dependant mechanism

“…We thus propose a model of RA-mediated IRS-1 degradation whereby RA first activates PKC-d, which in turn phosphorylates IRS-1 on serine residues, allowing for its subsequent recognition by the ubiquitin machinery. Breast cancer cells exhibit elevated levels of known ubiquitinated proteins, such as cyclin D1 (Wang et al, 1994), cyclin E (Lindahl et al, 2004), and IRS-1 (Rocha et al, 1997). Although the ubiquitin ligase, or E3, for cyclin D1 and IRS-1 remain unknown, future identification of these ligases, may lead to the development of compounds that specifically activate E3, thus inhibiting the accumulation of cyclin D1 and IRS-1 in breast tumors where these proteins are stabilized.…”