The cyclin D1 high and cyclin E high subgroups of breast cancer: separate pathways in tumorogenesis based on pattern of genetic aberrations and inactivation of the pRb node

Abstract

In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1 high tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E high tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E high tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1high and E high tumours. Using transfected cell lines overexpressing cyclin E, cyclin E high and D1 high tumours were mimicked and the cyclin D1 high cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E high cell lines obtained increased kinase activity without redirection of inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1 high and cyclin E high tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer. Oncogene (2002Oncogene ( ) 21, 4680 -4690. doi:10.1038 Keywords: breast cancer; cell cycle; cyclins; cdkinhibitors; pRb pathway; proliferation IntroductionThe G1/S transition in normal cells is a thoroughly controlled checkpoint where the important decision to initiate DNA-replication or not is taken (Draetta, 1994;Weinberg, 1995). As has been obvious the last couple of years, aberrations in G1/S regulatory proteins are common in various tumours and aberrant expression of cyclin E and D1, downregulation of p16 and p27 as well as mutation of the retinoblastoma gene (Rb) has frequently been observed in several cancers and it can be hypothesized that G1/S defects might be obligatory in tumour development (Landberg and Roos, 1997;Sandhu and Slingerland, 2000).Cyclin D1 links mitogenic signals to cell cycle progression through increased phosphorylation of pRb (Lukas et al., 1996). Amplification of the encoding cyclin D1 gene, CCND1, resulting in high cyclin D1 protein content, has been observed in a significant numbers of breast cancers and together with impaired cyclin D1 protein degradation potentially cause unbalanced phosphorylation of pRb (Sherr, 1996;Russell et al., 1999). The relation between cyclin D1 and in vivo pRb phosphorylation in primary breast cancer has nevertheless not been investigated. Overexpression of cyclin D1 has been associated with ERpositivity (Michalides et al., 1996;van Diest et al., 1997), while the relation to proliferation and survival has been without consensus (Jares et al., 1997;Barnes and Gillett, 1998). Nevertheless, simila...

Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

“…18,26 Proliferating cells are under the control of proteins in the cell cycle, and HIF-1a appears to be positively associated to proteins involved in S/G 2 -phase such as cyclin E and cyclin A2, but negatively associated to cyclin D1, which mainly functions in early G 1 -phase. This is in concordance with earlier published data, 35 but apart from the association to the cell cycle, this could also indicate that HIF-1a expression is correlated to a certain type of breast cancer with proliferative features and frequent overexpression of cyclin E. 36,37 HIF-1a has not been previously explored in relation to treatment prediction in a randomised treatment trial, but one breast cancer cell line study has demonstrated that hypoxia induces tamoxifen-resistant growth. 24 In our study we could not confirm this link between hypoxia and tamoxifen response, and both HIF1a low and high tumours appeared to respond to tamoxifen treatment.…”

Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

“…These results are particularly intriguing, since a recently published study noted a statistically significant correlation between cyclin E overexpression and decreased levels of Bcl-2 in breast tumors. 35 Overexpression of cyclin E in MCF7 cells results in a precipitous drop of Bcl-2, which is due to a decrease in mRNA levels (NKDFunpublished data). T47D cells have very low, but detectable levels of Bcl-2.…”

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

“…38,41,67 Most series have exhibited lower cyclin-D1 expression levels in BRCA1 than in sporadic tumors. 38,40,68 Cyclin-D1 expression in BRCA2 tumors has been found at an intermediate level between those of BRCA1 and sporadic tumors. For example, Osin et al 40 reported that cyclin D1 was expressed in 27% of BRCA2 tumors, compared with 5% in BRCA1 tumors and 35% in sporadic tumors.…”

“…These tumors had a more substantial lack of G1/S control, adopting an Rb-independent mechanism of cell proliferation. 68 …”