title: Frequent alterations of SLIT2-ROBO1-CDC42 signalling pathway in breast cancer: clinicopathological correlation.
abstract: The aim of the study was to understand the role of SLIT2-ROBO1/2-CDC42 signalling pathways in development of breast cancer (BC). Primary BC samples (n = 150), comprising of almost equal proportion of four subtypes were tested for molecular alterations of SLIT2, ROBO1, ROBO2 and CDC42, the key regulator genes of this pathway. Deletion and methylation frequencies of the candidate genes were seen in the following order: deletion, SLIT2 (38.6%) > ROBO1 (30%) > ROBO2 (7.3%); methylation, SLIT2 (63.3%) > ROBO1 (26.6%) >ROBO2 (9.3%). Majority (80%, 120/150) of the tumours showed alterations (deletion/methylation) in at least one of the candidate genes. Overall, alterations of the candidate genes were as follows: SLIT2, 75.3% (101/150); ROBO1, 45.3% (68/150); ROBO2, 15.3% (23/150). Significantly, higher alteration of SLIT2 locus was observed in triple negative breast cancer (TNBC) over HER2 subtype (P = 0.0014). Similar trend is also seen in overall alterations of SLIT2 and/or ROBO1, in TNBC than HER2 subtype (P = 0.0012); of SLIT2 and/or ROBO2 in TNBC than luminal A (P = 0.014) and HER2 subtype (P = 0.048). Immunohistochemical analysis of SLIT2, ROBO1/2 showed reduced expression, concordant with their molecular alterations. Also, high expression of total CDC42 (49/52; 94.2%) and reduced expression of phospho Serine-71 CDC42 (41/52; 78.8%) was observed. Coalterations of SLIT2 and/or ROBO1, SLIT2 and/or ROBO2 had significant association with reduced expression of phospho Serine-71 CDC42 (P = 0.0012-0.0038). Alterations of SLIT2 and/or ROBO1, reduced expression of phospho Serine-71 CDC42 predicted poor survival of BC patients. Results indicate the importance of SLIT2-ROBO1-CDC42 signalling pathway in predicting tumour progression.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, India.ckpanda.cnci@gmail.com.
authors.forename: Rittwika
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Nupur
authors.initials: N
authors.lastname: Mukherjee
authors.forename: Hemantika
authors.initials: H
authors.lastname: Dasgupta
authors.forename: Md Saimul
authors.initials: MS
authors.lastname: Islam
authors.forename: Neyaz
authors.initials: N
authors.lastname: Alam
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.forename: Priyobrata
authors.initials: P
authors.lastname: Das
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D011110:Polymorphism, Genetic; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010768:Phosphoserine; D018719:Erb-b2 Receptor Tyrosine Kinases; D011971:Receptors, Immunologic; D020764:cdc42 GTP-Binding Protein; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C498890:ROBO2 protein, human; C508053:ERBB2 protein, human