Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

Abstract

The CCND1 gene, a key cell-cycle regulator, is often altered in breast cancer, but the mechanisms underlying CCND1 dysregulation and the clinical significance of CCND1 status are unclear. We used real-time quantitative PCR and RT -PCR assays based on fluorescent TaqMan methodology to quantify CCND1 gene amplification and expression in a large series of breast tumours. CCND1 overexpression was observed in 44 (32.8%) of 134 breast tumour RNAs, ranging from 3.3 to 43.7 times the level in normal breast tissues, and correlated significantly with positive oestrogen receptor status (P=0.0003). CCND1 overexpression requires oestrogen receptor integrity and is exacerbated by amplification at 11q13 (the site of the CCND1 gene), owing to an additional gene dosage effect. Our results challenge CCND1 gene as the main 11q13 amplicon selector. The relapse-free survival time of patients with CCND1-amplified tumours was shorter than that of patients without CCND1 alterations, while that of patients with CCND1-unamplified-overexpressed tumours was longer (P=0.011). Only the good prognostic significance of CCND1-unamplified-overexpression status persisted in Cox multivariate regression analysis. This study confirms that CCND1 is an ER-responsive or ER-coactivator gene in breast cancer, and points to the CCND1 gene as a putative molecular marker predictive of hormone responsiveness in breast cancer. Moreover, CCND1 amplification status dichotomizes the CCND1-overexpressing tumors into two groups with opposite outcomes.

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

“…We used hTERT-positive MCF7 breast cancer cell lines 81 To evaluate the comparative effects of GTC365 versus BRACO-19 on the cooperative folding process, we carried out two different experiments. First, we compared the distribution of the different populations of small and large species using single-molecule experiments as described previously with GTC365 and BRACO-19 in the G138/139A mutant (Table S1).…”

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

“…However, whether this phenomenon is a simple marker of the disease state or whether aberrant cyclin D and/or E expression acts as a mediator of malignancy is under debate. Cyclin E gene amplification is infrequent, whereas cyclin D gene amplifications are often found in tumors (Barnes and Gillett, 1998;Malumbres and Barbacid, 2001;Bieche et al, 2002). Alteration of cyclin E in tumors can correspond to elevated expression of normally regulated protein or deregulated expression where the protein is expressed throughout the cell cycle rather than transiently at the G1/S-phase boundary.…”

Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis

“…Members of the Myc gene family directly transactivate hTERT (Wang et al, 1998;Wu et al, 1999), while Mad, an antagonizing binding partner of Myc, represses hTERT gene expression (Oh et al, 2000). High hTERT mRNA levels have been suggested to be linked to myc gene overexpression in various human cancers (Latil et al, 2000;Bieche et al, 2000;Sagawa et al, 2001). Introduction of HPV-E6 also stimulates the expression of hTERT through activation of unidentified transcription factors that share the binding site with Myc and Sp1 (Klingelhutz et al, 1996;Oh et al, 2001).…”