Mathias Uhlén

Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer

Background:Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer. In this study, we investigated the prognostic impact of PODXL expression in colorectal cancer (CRC).Methods:Using tissue microarrays and immunohistochemistry, PODXL expression was evaluated in 536 incident CRC cases from a prospective, population-based cohort study. Kaplan–Meier analysis and Cox proportional hazards modelling were used to assess the impact of PODXL expression on cancer-specific survival (CSS) and overall survival (OS).Results:High PODXL expression was significantly associated with unfavourable clinicopathological characteristics, a shorter CSS (hazard ratio (HR)=1.98; 95% confidence interval (CI) 1.38–2.84, P<0.001) and 5-year OS (HR=1.85; 95% CI 1.29–2.64, P=0.001); the latter remaining significant in multivariate analysis (HR=1.52; 95% CI 1.03–2.25, P=0.036). In addition, in curatively resected stage III (T1–4, N1–2, M0) patients (n=122) with tumours with high PODXL expression, a significant benefit from adjuvant chemotherapy was demonstrated (pinteraction =0.004 for CSS and 0.015 for 5-year OS in multivariate analysis).Conclusion:Podocalyxin-like 1 expression is an independent factor of poor prognosis in CRC. Our results also suggest that PODXL may be a useful marker to stratify patients for adjuvant chemotherapy.

CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

SCF (Skp1/Cul1/F‐box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F‐box protein, FBXO28 that controls MYC‐dependent transcription by non‐proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2‐mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F‐box mutant unable to support MYC ubiquitylation results in an impairment of MYC‐driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK‐FBXO28‐MYC axis as a potential molecular drug target in MYC‐driven cancers, including breast cancer.

Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer

Background:Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer.Methods:Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n=100 (Cohort I) and n=343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed.Results:Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR=2.25 in Cohort I and 3.10 in Cohort II, adjusted HR=2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR=4.36, adjusted HR=2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR=6.19, adjusted HR=4.60) and DSS (unadjusted HR=8.34, adjusted HR=7.16).Conclusion:Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

P1.52 BIO-NMD: Discovery and validation of biomarkers for neuromuscular diseases (NMDs) – An EU funded FP7 project

www.bio-nmd.eu Volker Straub1, Annemieke Aartsma-Rus2, Cristina Al-Khalili Szigyarto3, Christophe Beroud4, Paolo Bonaldo5, Paola Borgiani6, Paola Braghetta5, Amina Chaouch1, Sebahattin Cirak7, Roseline Favresse8, Nikolai Daraselia9, Cecilia Gelfi10, Peter A.C. ’t Hoen2, Ekaterina Kotelnikova9, Yannick Le Priol9, Hanns Lochmuller1, Jenny Morgan7, Francesco Muntoni7, Giuseppe Novelli6, Nicoletta Paolillo6, Raimo Tanzi11, Cathy Turner1, Mathias Uhlen3, Alessandra Ferlini12 On behalf of the BIO-NMD consortium

Systematic validation of novel breast cancer progression-associated biomarkers via high-throughput antibody generation and application of tissue microarray technology

Systematic validation of novel breast cancer progression-associated biomarkers via high-throughput antibody generation and application of tissue microarray technology : an initial report