Sphingosine Kinase Type 1 (SPHK-1) and Sphingosine-1-Phosphate Receptor 1 (S1PR1/EDG1) Positive Breast Carcinomas Are Associated with Increased Incidence of Distant Metastases
Hope T Richard, Joseph P Bergeron, Jorge A Almenara, Michael O Idowu. Virginia Commonwealth University, Richmond, VA
Background: Sphingosine Kinase Type 1 (SPHK-1) and its metabolite, sphingosine-1-phosphate receptor 1 (S1P/EDG-1), have been implicated in cell growth, apoptosis suppression, and angiogenesis. Overexpression of SPHK-1 with concomitant increase in EDG-1 induces an anti-apoptotic effect, and recent studies suggest a relationship with poor outcome in breast carcinoma patients in this setting. We evaluated the relationship between SPHK-1/EDG-1 expression and distant mets along with other clinicopathologic parameters including Ki-67, local recurrence, triple negative hormone receptor (HR) status, and lymph node (LN) status.
Design: Clinical outcome and pathologic characteristics of breast cancer cases from 1992 to 2008 were reviewed. A minimum of 60 mos of follow-up was required for inclusion of cases without recurrence or metastases. Tissue microarrays (TMA) were created by obtaining 1 mm cores in triplicate from different areas of the tumor using an automated TMA system (Beecher ATA-27). Specimens were stained with rabbit polyclonal antibodies to SPHK-1 and EDG-1 (Abcam, Ma USA). For EDG-1, moderate to intense membranous staining was positive; for SPHK-1 moderate to intense cytoplasmic and/or nuclear membrane staining was pos. Cases were independently scored by two pathologists. Statistical significance was determined by a Chi-squared test.
Results: 278 SPHK-1 cases and 255 EDG-1 cases were scorable. Median follow-up for all cases was 72 mos, ranging from 12 to 228 mos. 85 SPHK-1 cases and 79 EDG-1 cases having distant mets and/or loco-regional recurrence were identified. A higher fraction of cases with distant mets was associated with SPHK-1 and EDG-1 positivity (51 vs 34, p= 0.009 and 60 vs 19, p=0.05), respectively. Additionally, EDG-1 positivity was associated with high Ki-67 (>30%)(p=0.016), whereas SPHK-1 positivity was associated with triple negative HR status (p=0.007) and axillary LN positivity (p=0.03).
|SPHK1/EDG1||SPHK1 pos||SPHK1 neg||EDG1 pos||EDG1 neg|
|% dist mets (n=85/79)||60% (51)||40% (34)||76% (60)||24% (19)|
|% loc recur (n=32/27)||63% (20)||37% (12)||74% (20)||26% (7)|
|% grade III (n=108/98)||63% (68)||37% (40)||69% (68)||34% (30)|
|% high Ki67 (n=93/89)||68% (63)||32% (30)||74% (66)||26% (23)|
|% triple neg (n=73/66)||55% (40)||45% (33)||68% (45)||32% (21)|
|% LN pos (n=115/104)||72% (83)||28% (32)||71% (74)||29% (30)|