MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer
Introduction
Profiling of tumours through microarray technologies has greatly improved over the past decades, and it has been used as a powerful tool in expanding knowledge on cancer etiology. Gene expression profiles provide specific molecular signatures containing information able to explain the mechanisms of tumour development and progression, and they open up new possibilities in predicting clinical outcome or response to treatment. However, although these technologies have provided most of the new biomarkers with potential use for diagnosis, drug development, and tailored therapy, they have not exhaustively elucidated all the detailed mechanisms at tumour origin, thus suggesting that tumourigenesis may occur through novel or poorly characterised pathways.
In recent years new players have been revealed in the biology of cancer: microRNAs (miRNAs), a small class of non-coding RNAs able to regulate gene expression at post-transcriptional level, binding through partial sequence homology the 3′ untranslated region (3′ UTR) of target mRNAs, and causing a block of translation and/or mRNA degradation.1 Several studies have indeed demonstrated that miRNAs are highly specific for tissue and developmental stages, that they play important roles in essential processes, such as differentiation, cell growth, stress response and cell death2, 3, and are involved in several human diseases, including cancer. Microarray technologies have been applied to this new class of molecules as a tool to recognise miRNAs differentially expressed between normal and tumour samples, as reviewed by Calin and Croce.4 Moreover, recent exciting and encouraging data demonstrated how miRNAs can be associated with well-defined clinico-pathological features and outcome in different tumour types.
We will describe the experimental evidence underlying the involvement of miRNAs in breast cancer, and we will discuss their possible use as markers of diagnosis and prognosis, and eventually as new targets or tools of a specific therapy.
Section snippets
MiRNAs are aberrantly expressed in human breast cancer
Genome-wide miRNA expression studies have been providing over recent years an increasingly detailed portrait of the involvement of these small regulatory molecules in human cancer.
The first reports describing the existence of a miRNA signature characterising human breast cancer were published in 20055, 6, 7, suggesting the involvement of miRNAs in the pathogenesis of this human neoplasm. Lu and colleagues7 used a beads-based flow cytometric technique to evaluate the miRNA profiling in different
miRNA expression regulation in breast cancer: Genomic changes and epigenetic mechanisms
Several studies have investigated the molecular alterations leading to an aberrant miRNA expression in cancer, identifying chromosomal aberrations10, 11, epigenetic mechanisms or abnormalities in miRNA-processing genes.
In our miRNA expression study5, we suggested the involvement of genomic alterations as the mechanism of miRNA expression regulation, analysing their chromosomal localization: miR-125b, for example, down-modulated in breast cancer, is located at chromosome 11q23-24, one of the
Biological effects and targets: New players in the biology of breast cancer
Having selected candidate miRNAs likely to be involved in the biology and development of breast cancer, the important issue then is to investigate their functional role.
Being that miRNAs are able to explicate their function through regulation of specific mRNAs, a great interest has always been addressed to the identification of target molecules: let-7 suppresses RAS19 and HMGA220,21; miR-15 and miR-16 target Bcl-222; miR-372 and miR-373 are novel oncogenes in testicular germ cell tumours that
miRNAs as diagnostic and prognostic tools
An increasing and encouraging number of evidences demonstrate how miRNAs can correlate with well-defined clinico-pathological features and disease outcome: in CLL, a unique signature of 13 miRNAs could discriminate tumours according to prognosis and disease progression43; in lung cancer, poor prognosis correlates to the expression of miR-155 (high) and let-7a-2 (low)44; in human pancreatic cancer, Bloomston and colleagues45 identified a miRNA, miR-196a-2, that may significantly impact survival.
miRNAs as possible targets or tools for therapy
The potential usefulness of a miRNA-based therapy in cancer is now being exploited: in breast cancer, the reduced migration and invasion capacities induced by miR-125 or the use of anti-miR-21 to elicit a pro-apoptotic response are important examples.
Moreover, miRNAs involved in specific networks, such as the apoptotic pathway, the HER family-driven or ER-mediated signalling, could likely influence the response to chemotherapy or to targeted therapies, such as Trastuzumab, the monoclonal
Concluding remarks
Over the past decades, great efforts have been spent to elucidate the molecular mechanisms involved in breast cancer and to identify molecules useful as bio-markers of diagnosis or prognosis.
Gene profiling studies have represented a powerful tool to address this issue: different prognostic tests are available according to gene expression, such as the MammaPrint, developed by Van’t Veer and colleagues60, which is able to predict relapse according to the expression of genes regulating cell cycle,
Conflict of interest statement
According to the rules of this journal, I declare that:
- (1)
All the authors declare that they participated in the planning, execution, or analysis of the study.
- (2)
All the authors declare that they have seen and approved the final version.
- (3)
All the authors declare that they have no conflict of interest in connection with this paper.
Acknowledgements
Dr. Croce is supported by Program Project Grants from the National Cancer Institute. Dr. Iorio is supported by a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC). This work was partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC).
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