microRNA associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer
Menée sur une cohorte de 207 cas de cancer du sein (durée de suivi : 10 ans) à l'aide d'une analyse conjointe de l'expression de micro-ARN et d'ARN messager, cette étude identifie des micro-ARNs associés à la progression tumorale
microRNA expression profiling plays an emerging role in cancer classification and identification of therapeutic strategies. In this study, we have evaluated the benefits of a joint microRNA-mRNA analysis in breast cancer. Matched mRNA and microRNA global expression profiling was performed in a well-annotated cohort of 207 cases with complete 10-year follow-up. Penalized Cox regression including microRNA expression, mRNA expression and clinical covariates was used to identify microRNAs associated with distant relapse-free survival (DRFS) that provide independent prognostic information, and are not simply surrogates of previously identified prognostic covariates. Penalized regression was chosen to prevent over-fitting. Furthermore, microRNA-mRNA relationships were explored by global expression analysis, and exploited to validate results in several published cohorts (N=592 with DRFS, N=1050 with recurrence-free survival). Four microRNAs were independently associated with DRFS in oestrogen receptor (ER)-positive (3 novel and 1 known - miR-128a) and 6 in ER-negative (5 novel and 1 known - miR-210) cases. Of the latter, miR-342, -27b and -150 were prognostic also in triple receptor negative tumours. Coordinated inhibition of target expression by prognostic microRNAs strengthened these results; the most significant being miR-210, -128a and -27b, whose targets were prognostic in meta-analysis of several cohorts. In addition, miR-210 and -128a showed coordinated expression with their cognate pri-microRNAs, which were themselves prognostic in independent cohorts. Our integrated microRNA-mRNA global profiling approach has identified microRNAs independently associated with prognosis in breast cancer Furthermore it has validated known and predicted microRNA-target interactions, and elucidated their association with key pathways that could represent novel therapeutic targets.
Cancer Research 2011