title: Geminin predicts adverse clinical outcome in breast cancer by reflecting cell-cycle progression.
abstract: Geminin inhibits DNA replication by preventing Cdt1 from loading minichromosome maintenance (MCM) proteins onto DNA. The present study has investigated whether the frequency of geminin expression predicts clinical outcome in breast cancer. Immunohistochemistry was used first to examine geminin expression in normal and malignant breast tissue (n = 67). Correlations with cell-cycle parameters, pathological features, and clinical outcome were then determined using an invasive breast carcinoma tissue microarray (n = 165). Breast carcinomas were scanned for mutations (n = 61) and copy number imbalances (n = 241) of the geminin gene. Finally, the cell cycle distribution of geminin in breast cancer cells was investigated in vivo and in vitro. Despite a putative tumour suppressor function, it was found that increased geminin expression is a powerful independent indicator of adverse prognosis in invasive breast cancer. Both poor overall survival (p = 0.0002) and the development of distant metastases (p = 0.005) are predicted by high geminin expression, which performs better in this patient cohort than traditional factors currently used to determine prognosis and appropriate therapy. No mutations or deletions of the geminin gene and no evidence that a high frequency of protein expression is related to gene amplification were found. It is shown that geminin is expressed from S to M phase in breast carcinoma tissue and cell lines, disappearing at the metaphase--anaphase transition. While MCM proteins identify all non-quiescent cells, geminin identifies the sub-fraction that have entered S phase, but not exited mitosis, thereby indicating the rate of cell-cycle progression. It is suggested that this explains its unexpected value as a prognostic marker in breast cancer.
authors.affiliation: Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, UK. mg322@cam.ac.uk
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.forename: Kiku-E K
authors.initials: KE
authors.lastname: Tachibana
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Grace
authors.initials: G
authors.lastname: Callagy
authors.forename: Mark A
authors.initials: MA
authors.lastname: Madine
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Vowler
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pinder
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Laskey
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D004261:DNA Replication / Q000235:genetics; D005260:Female; D064248:Geminin; D005784:Gene Amplification / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C577995:GMNN protein, human; D064248:Geminin