Sasagu Kurozumi1,2, Chitra Joseph1, Sultan Sonbul1, Mohammed A Aleskandarany1,3, Marian Pigera1, Mansour Alsaleem1, Sami Alsaeed1, Yousif Kariri1, Christopher C Nolan1, Maria Diez-Rodriguez1, Simon Johnston1, Nigel P Mongan4,5, Takaaki Fujii2, Ken Shirabe2, Stewart G Martin1, Ian O Ellis1, Andrew R Green1, Emad A Rakha6,7,8. 1. Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK. 2. Department of General Surgical Science, Gunma University, Graduate School of Medicine, Gunma, Japan. 3. Faculty of Medicine, Menoufyia University, Shebin al Kawm, Egypt. 4. Cancer Biology and Translational Research, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK. 5. Department of Pharmacology, Weill Cornell Medicine, New York, USA. 6. Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK. Emad.Rakha@nottingham.ac.uk. 7. Faculty of Medicine, Menoufyia University, Shebin al Kawm, Egypt. Emad.Rakha@nottingham.ac.uk. 8. Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, NG5 1PB, UK. Emad.Rakha@nottingham.ac.uk.
Abstract
BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.
BACKGROUND: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. METHODS: 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). RESULTS: 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). CONCLUSIONS: High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.
Entities:
Keywords:
E-cadherin; Invasive breast cancer; Lymphovascular invasion; Ras association and pleckstrin homology domains 1; Re-epithelialisation