Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway in breast cancer: clinicopathological correlation

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• 作者：RITTWIKA BHATTACHARYA ; NUPUR MUKHERJEE ; HEMANTIKA DASGUPTA…
• 关键词：breast cancer ; alterations of SLIT2–ROBO1 signalling ; active CDC42 ; pSer71 ; CDC42
• 刊名：Journal of Genetics
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：95
• 期：3
• 页码：551-563
• 全文大小：5,884 KB
• 刊物主题：Life Sciences, general; Microbial Genetics and Genomics; Plant Genetics & Genomics; Animal Genetics and Genomics; Evolutionary Biology;
• 出版者：Springer India
• ISSN：0973-7731
• 卷排序：95

文摘

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.