Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays.
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.
Bièche
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Laboratoire de Génétique Moléculaire-UPRES JE 2195, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes-Paris V, 4 Avenue de l'Observatoire, F-75006 Paris, France. ivan.bieche@pharmacie.univ-paris5.fr
Olivi
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Noguès
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Vidaud
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Lidereau
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D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D011960:Receptors, Estrogen / Q000032:analysis; D012016:Reference Values; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
D017931:DNA Primers; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D019938:Cyclin D1