title: Cortactin gene amplification and expression in breast cancer: a chromogenic in situ hybridisation and immunohistochemical study.
abstract: Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the 'driver' of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification. The aims of this study are to define whether CTTN is consistently co-amplified with the main core of the 11q13 amplicon, whether it is consistently overexpressed when amplified and to determine correlations between CTTN amplification and overexpression with clinicopathological features of breast cancers and survival of breast cancer patients. CTTN and CCND1 chromogenic in situ hybridisation (CISH) probes and a validated monoclonal antibody against CTTN were applied to a tissue microarray of a cohort of breast cancers from patients treated with anthracycline-based chemotherapy. CTTN and CCND1 amplifications were found in 12.3 and 12.4% of cases, respectively. All cases harbouring CTTN amplification also displayed CCND1 amplification. High expression of CTTN was found in 10.8% of cases and was associated with CTTN amplification, expression of 'basal' markers and topoisomerase IIα. Exploratory subgroup analysis of tumours devoid of 11q13 amplification revealed that high expression of CTTN in the absence of CTTN gene amplification was associated with lymph node negative disease, lack of hormone receptors and FOXA1, expression of 'basal' markers, high Ki-67 indices, p53 nuclear expression, and basal-like and triple negative phenotypes. CTTN expression and CTTN gene amplification were not associated with disease-, metastasis-free and overall survival. In conclusion, CTTN is consistently co-amplified with CCND1 and expressed at higher levels in breast cancers harbouring 11q13 amplification, suggesting that CTTN may also constitute one of the drivers of this amplicon. CTTN expression is not associated with the outcome of breast cancer patients treated with anthracycline-based chemotherapy.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.forename: Maria-Angeles
authors.initials: MA
authors.lastname: Lopez-Garcia
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Maryou B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Radost
authors.initials: R
authors.lastname: Vatcheva
authors.forename: Paul
authors.initials: P
authors.lastname: Wilkerson
authors.forename: Daniel
authors.initials: D
authors.lastname: Wetterskog
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D002863:Chromogenic Compounds; D002880:Chromosomes, Human, Pair 11; D051356:Cortactin / Q000032:analysis* / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D004076:Digoxigenin; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008131:London; D008408:Mastectomy; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D013997:Time Factors; D046888:Tissue Array Analysis / Q000379:methods*; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C495868:CTTN protein, human; D002863:Chromogenic Compounds; D051356:Cortactin; D019938:Cyclin D1; D004076:Digoxigenin