title: Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer.
abstract: Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G1 phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients' response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.83) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).
authors.affiliation: Linköping University, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, KEF/oncology laboratory, University Hospital, SE-581 85 Linköping, Sweden. marie.ahnstrom@liu.se
authors.forename: Marie Ahnström
authors.initials: MA
authors.lastname: Waltersson
authors.forename: Marie Stenmark
authors.initials: MS
authors.lastname: Askmalm
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.forename: Lambert
authors.initials: L
authors.lastname: Skoog
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D019927:Cyclin E / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016160:Retinoblastoma Protein / Q000235:genetics; D013997:Time Factors
chemical_list: D019927:Cyclin E; D016160:Retinoblastoma Protein