Title: MicroRNAs methylation and expression profiling for identification of breast cancer patients at high risk to develop distant metastases.
Manel ESTELLER (Spain) Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet de Llobregat, Barcelona
Paola PARRELLA (Italy) Fondazione Casa Sollievo della Sofferenza - I.R.C.C.S., San Giovanni Rotondo (FG)
Ella EVRON (Israel) Assaf Harofeh Medical Center, Zerifin
Breast cancer is the most common cancer in women and its mortality is primarily caused by metastatic spread to distant organs. Thus, it is necessary to identify and validate metastasis molecular biomarkers at the time of surgery to predict and monitor breast cancer progression.
MicroRNAs (miRNAs) are a class of small cellular RNAs that modulate gene expression at post-transcriptional level. They can act as oncogenes or tumor-supressor genes, playing a role in all steps of tumorigenesis. MiRNAs up or down-regulation (mainly by promoter DNA hypermethylation) and metastatic spread have been widely investigated. However, only small and retrospective studies have been completed in a clinical setting to date. Here, we propose to evaluate the potential role as predictive markers of several candidate miRNAs already linked to metastatic process (selected from in vitro and limited sample size studies). We will analyze the correlation of both expression and DNA methylation markers with distant metastasis free survival in a large retrospective cohort (n=352). The best candidate markers will be validated in two independent and extensive (n=500 and n=300) prospective cohorts. Additionally, miRNA biomarkers both in plasma and Circulating Tumor Cells will be evaluated for treatment monitoring and early metastases detection. Of note, as DNA methylation is potentially reversible and several investigations with anticancer treatments targeting miRNAs are currently ongoing, this proposal may also identify novel therapeutic targets for high risk breast cancer patients.
The consortium partners guarantee the feasibility and strength of the proposal. The coordinator, Dr Esteller, has a wide and successful experience in epigenetic research and in the coordination of European projects. The clinical teams have a solid background in breast cancer clinical and epigenetic studies. Altogether, the expertise of the partners and the possibility of using large retrospective, prospective and cross-validation cohorts may circumvent the limitations of the small studies completed to date in the search for miRNAs metastasis biomarkers.
Breast cancer is the most common cancer in women and its mortality is primarily caused by metastatic spread to distant organs. Thus, it is necessary to identify and validate metastasis molecular biomarkers at the time of surgery to predict and monitor breast cancer progression. MicroRNAs (miRNAs) are a class of small noncoding RNAs and play a critical role in cell biology by regulating gene expression at the post-transcriptional level. They can act as oncogenes or tumor-suppressor genes, playing a role in all steps of tumorigenesis. Aberrant DNA methylation is an epigenetic transcriptional silencing mechanism that can be associated as one of the mechanisms of down-regulation of miRNAs, which is currently emerging as a common hallmark of cancer. Metastasis is the major cause of cancer mortality, and an important clinical problem that has been widely investigated. However, only small and retrospective studies have been completed in a clinical setting to date.
BREMIR’s research project is based on the identification of a panel of microRNAs as biomarkers that could be predictive of distant metastasis in breast cancer patients. In order to achieve this aim, we analyzed a panel of miRNAs by gene expression and DNA methylation analysis of breast cancer samples at early-stage of progression with low risk of relapse. We identified and select 11 miRNAs associated with disease progression and metastasis development. Next, a new set of miRNAs related to poor prognosis were selected and validated. The results are promising in overexpressed miRNAs as predictive biomarkers, opening the range of possibilities for a better clinical management of breast cancer patients.
Overall, we identified a new set of predictive miRNAs that determine the metastatic potential of breast cancer tumors and may ultimately help select patients more likely to develop breast cancer distant metastasis.
(Project funded under JTC 2013)