Abstract
Ras association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and, therefore, may play a key role in carcinogenesis and metastasis. We, herein, investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts. The clinicopathological and prognostic significance of RAPH1 was assessed at the genomic and transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039) and the results were validated using the Molecular taxonomy of breast cancer international consortium (METABRIC) cohort (n = 1980). RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n = 1040). In both the TCGA and METABRIC cohorts, RAPH1 mRNA expression and RAPH1 copy number alteration were strongly correlated. RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. RAPH1 mRNA overexpression was a significant predictor of a poor prognosis (Hazard ratio 3.88; p = 0.049). High RAPH1 protein expression was associated with higher grade tumours with high proliferation index, triple negative phenotype and high E-cadherin expression. High RAPH1 protein expression was an independent predictor of shorter survival (Hazard ratio 4.37; p = 0.037). High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.
Highlights
Recent developments in diagnostic accuracy and drug therapies have improved outcomes in early-stage breast cancer (BC)
High Ras association and pleckstrin homology domains 1 (RAPH1) mRNA overexpression was associated with higher CDH1 (TCGA: p < 0.0001; METABRIC: p = 0.0096), lower TGFβ1 (TCGA: p < 0.0001; METABRIC: p = 0.0011), lower KRT6C (TCGA: p = 0.0059; METABRIC: p = 0.026) and higher CD44 (TCGA: p < 0.0001; METABRIC: p < 0.0001) expression s in both the The Cancer Genome Atlas (TCGA) and METABRIC cohorts (Table 1)
Patients with high RAPH1 mRNA expression had worse prognosis than those with low RAPH1 mRNA expression in TCGA cohort, this was not observed in the METABRIC validation cohort (Supplementary Figure 3)
Summary
Recent developments in diagnostic accuracy and drug therapies have improved outcomes in early-stage breast cancer (BC). Ras association and pleckstrin homology domains 1 (RAPH1), referred to as lamellipodin (LPD) [3], acts as a downstream effector of the Ras pathway [4], which plays an important role in epithelial-mesenchymal transition (EMT) [5, 6]. Ras association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and may play a key role in carcinogenesis and metastasis. We investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts. RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n=1040). RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. CONCLUSIONS: High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer
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