Aberrant Expression, and Potency as Cancer Markers/Targets, of Splicing Regulators in Breast Cancer
M Lacroix-Triki, JF Dupuy, F Dalenc, S Dejean, P Besse, H Roche, P Rochaix, S Vagner. Institute Claudius Regaud, Toulouse, France; Institut de Mathmatiques de Toulouse, Toulouse, France
Background: SR splicing regulator and hnRNP heterogeneous nuclear ribonucleoprotein proteins are mRNA binding proteins that regulate several aspects of mRNA metabolism, from splicing/polyadenylation processes to translational control. Since ample evidences exist to demonstrate a connection between alternative splicing and cancer, we have examined the expression of several of these regulators in breast cancer.
Design: Four SR (9G8, SC35, SRp20, ASF/SF2) and 1 hnRNP (hnRNP A1) proteins were analyzed using tissue microarrays of 277 invasive breast carcinomas. Immunostainings were interpreted using a score combining the percentage of stained cells and the intensity of staining. Staining localization, clinical and histopathological data were recorded for each case.
Results: The study population showed the following characteristics: 9-year median follow-up, median age 54 years, median tumor size 18mm, invasive ductal carcinoma (77.3%), histological grade divided in grade I (12.3%), grade II (39%) and grade III (45.8%), node negative disease in 56.7%, ER+ tumor in 65%, PR+ tumor in 58.4%, and 12% of HER2 over-expressing tumors. Two of the 5 proteins studied, hnRNP A1 and SC35, were statistically correlated to survival. A high hnRNP A1 expression was correlated to poor outcome when considering relapse-free survival (p=0.05), distant metastasis-free survival (p=0.03) and overall survival (p=0.02). A low SC35 expression was associated to poor prognosis when considering relapse-free survival in the overall population (p=0.04), but also in the node negative subgroup (p=0.04). Combination of a high hnRNP A1 expression and a low SC35 expression was strongly correlated to poor prognosis (relapse-free survival, p=0.01 in the overall population and p=0.006 in the node negative subgroup). In addition, the hnRNP A1 subcellular localization was highly correlated to prognosis, with identification of a subset of poor prognosis patients showing strong hnRNP A1 cytoplasmic staining.
Conclusions: Aberrant expression of key-proteins regulating post-transcriptional control of gene expression is thus correlated to clinical outcome in breast cancer. Such key-factors, participating to the protein diversity, may provide new prognostic or therapeutic target possibilities.
Monday, March 9, 2009 1:00 PM
Poster Session II # 42, Monday Afternoon