title: Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.
abstract: The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.
authors.affiliation: Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Bostner
authors.forename: M
authors.initials: M
authors.lastname: Ahnström Waltersson
authors.forename: T
authors.initials: T
authors.lastname: Fornander
authors.forename: L
authors.initials: L
authors.lastname: Skoog
authors.forename: B
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: O
authors.initials: O
authors.lastname: Stål
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D003520:Cyclophosphamide / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005784:Gene Amplification; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics; D017698:Postmenopause; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use*; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D056741:Cyclin D; D016213:Cyclins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013629:Tamoxifen; D003520:Cyclophosphamide; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D005472:Fluorouracil; D008727:Methotrexate