Clinical Role of Total Osteopontin and Osteopontin-c mRNA in Subtypes of Breast Carcinoma
Fernando Ortiz-Martinez, Francisco J Gutierrez-Avino, Daniel Giner, Daniel Ciprian, Leire Andres, Encarna Adrover, F Ignacio Aranda, Enrique Lerma, Gloria Peiro. Hospital General Universitari, Alacant, Spain; Hospital de Cruces, Barakaldo, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Background: Osteopontin (OPN), a secreted phosphorylated glycoprotein, promotes cell tumor progression binding to integrins and CD44 cell receptors, then regulating multiple signaling pathways like Wnt/B-catenin/Tcf4, PI3K/Akt or JAK2/STAT3. OPN overexpression has been correlated with metastasis and adverse outcome in several neoplasms. In breast carcinoma (BC) the expression of total OPN (OPN-t) mRNA and its splicing variant c (OPN-c) (a suggested marker for transformed cells) as well as their clinical role have not been extensively evaluated.
Design: 305 BC samples were first classified immunohistochemically into Luminal A and B, HER2 or triple negative (TN)/basal-like phenotypes. Total mRNA was extracted from preselected tumor areas of paraffin-embedded tissue and retrotranscripted to cDNA. Quantitative real-time PCR was performed to analyze OPN-t and OPN-c levels using TaqMan® Gene Expression Assays. A mix of 10 normal mammary tissue mRNA was used as a calibrator, and PUM1 as reference gene to normalize OPN-t and OPN-c expression. Relative mRNA levels were determined using the ΔΔCT method. Correlations between OPN-t and OPN-c results with clinico-pathological factors and outcome were evaluated.
Results: Median patients' age was 57 years (range 23-89) and the median follow-up 83 months (range 6-281). OPN-t mRNA overexpression (fold change ≥5) was detected in 74% samples (226/305). Among them, tumors were more frequently HER2 (43%) and TN/basal-like (33%) subtypes (p=0.004), with positive lymph-node status (40%; p=0.025), presenting in patients >50 years (70%, p=0.046), and a trend toward grade 3 (66%; p=0.07) and presence of necrosis (50%, p=0.15). OPN-c was overexpressed (≥2 fold change) in 53% samples (108/203) associated with TN/basal-like subtype (46%; p=0.002). Patients with increased OPN-t mRNA tumor levels had shorter overall survival (74% vs 84%; p=0.006), especially those with TN/basal-like (65% vs 82%; p=0.052) (Kaplan-Meier; log rank).
Conclusions: In our series of BC, increased OPN-t mRNA was associated with poor prognostic factors, HER2 and TN/basal-like subtypes and shorter survival. Moreover, OPN-c was specifically related with TN/basal-like. Therefore, novel therapeutic strategies against OPN might be a valid approach for treatment of aggressive BC phenotypes.
Supported by Grants FCVI-HGUA (PI-C/2008/02), ACOMP/2009/195 and GE-018/09
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 52, Wednesday Morning