MMI Clinician Scientist Fellow involved in ground-breaking breast cancer research

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MMI Clinician Scientist Fellow involved in ground-breaking breast cancer research

Ground breaking research from the Breast Cancer Research Group in NUI Galway, demonstrating that microRNAs are measurable in the blood of breast cancer patients and suggesting that a particular microRNA can be used as a breast cancer specific tumour marker, was well received at the recent annual San Antonio Breast Cancer Symposium, and was reported on the front page of the Irish Times (see http://www.irishtimes.com/newspaper/health/2009/1222/1224261097798.html). The work was led by Professor Michael Kerin, presented by Dr Helen Heneghan and co-authored by Dr Nicola Miller and Dr John Newell. Research by MMI Clinician Scientist Fellow Dr Aoife Lowery formed much of the background to this study. Dr Miller describes the research below.

MicroRNAs and cancer
The incidence of breast cancer is increasing worldwide. In the context of increasing disease burden, translational research is of vital importance to clinical advancement. The evolution of high throughput technologies, such as microarray gene expression profiling, have facilitated breakthroughs that have altered traditional thinking regarding breast cancer as a disease entity. The discovery of mi(cro)RNAs as regulators of gene expression represents a paradigm changing event in biology and medicine. It is now recognised that miRNAs are profoundly important in carcinogenesis through their regulation of oncogenes and tumour suppressor genes. This knowledge, coupled with the fact that miRNA expression profiles have shown superior accuracy to messenger RNA at classification of human cancer according to developmental lineage and differentiation status, indicates that understanding miRNA biology will be integral to an improved understanding of breast cancer biology. It is likely that uncovering the miRNA layer of genetic regulation will be a crucial step in the development of accurate prognostication and targeted therapy in breast and other cancers.

Developing microRNA expression signatures to classify breast tumours
In order to comprehensively analyse miRNA expression in breast tumours, global miRNA profiling was undertaken in early stage matched breast tumour specimens in collaboration with Dr. Vladimir Beněs at EMBL, Heidelberg. Analysis of microarray expression data was performed in collaboration with Dr. Graham Ball at Nottingham Trent University. Artificial Neural Networks (ANN) were chosen as the bioinformatics tool due to their ability to cope with complex data, their potential for modelling data of high nonlinearity and their ability to identify patterns within a dataset that can discriminate between subgroups.

Using this approach miRNA signatures predictive of ER, PR and HER2/neu receptor status were generated, which was the first report of ANN analysis of miRNA expression data (Lowery et al, 2009). These clinical parameters were chosen as they remain the current prognostic markers used in breast cancer; clinical decisions regarding adjuvant therapy and the clinically relevant breast cancer sub-groupings are based broadly on ER, PR and HER2/neu receptor status. Our results highlight the potential for developing miRNA expression signatures as diagnostic and prognostic tools for breast cancer. The capacity of miRNA expression profiles to classify breast tumours according to the clinicopathological variables currently used to predict disease progression, indicates that these signatures may contribute to improved prognostication and selection of patients for adjuvant therapy, as has shown promise with mRNA signatures.

Assessing the potential for circulating microRNAs as breast cancer biomarkers
Inherent characteristics of miRNAs such as their lower complexity, tissue specific expression profiles and their stability make these molecules ideal candidates as biomarkers reflective of physiological and pathological states. Recent blood-based miRNA profiling studies have generated the concept that circulating miRNAs hold much potential as novel non-invasive biomarkers for cancer and other disease processes. These preliminary reports have suggested the clinical utility of systemic miRNA analysis for several cancers including prostate, colorectal, lung, and lymphomas, as well as in the management of non-malignant diseases such as diabetes mellitus and drug-induced hepatitis. To date there has been no report regarding their usefulness, if any, in breast cancer management. Our aim was to assess the potential for circulating miRNAs as novel minimally invasive breast cancer biomarkers.

Real-time PCR analysis was carried out to determine the quantities of a panel of candidate miRNAs in tissue and blood specimens from patients with breast cancer and in age-matched disease-free control individuals. We found that cancer specific miRNAs were detected and significantly altered in the circulation of breast cancer patients compared to healthy controls. In particular two systemic miRNAs were elevated in breast cancer patients and could discriminate breast cancer cases from controls with high specificity and sensitivity. Furthermore, blood miRNA levels were even elevated in patients with in-situ disease, the earliest form of breast cancer, suggesting a possible role for circulating miRNAs as cancer screening tools (Heneghan et al, 2010).

Additional evidence from our study that supports systemic miRNAs as ideal cancer biomarkers:
1. Tumour and blood miRNA levels reflected tumour burden with higher levels of miRNA found in patients with more advanced stage of disease.
2. Circulating levels of miRNAs decreased in cancer patients post-operatively, to levels comparable with control subjects, following curative tumour resection
3. Specific circulating miRNAs correlated with certain clinicopathological variables, namely nodal status and oestrogen receptor status.

While further prospective evaluation of blood-based miRNAs, in breast and other cancers is needed to validate these findings, our results suggest that there is a very real and imminent potential for circulating miRNAs to fill the void in clinical practice for a sensitive and specific minimally invasive biomarker, to aid in the diagnosis, prognostication and follow-up of breast cancer.
Dr Aoife Lowery holds an MMI Clinician Scientist Fellowship. The MMI Clinician Scientist Fellowship Programme is funded through PRTLI Cycle 4 administered by the Higher Education Authority.

References

1: Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, Benes V, Schmidt S, Blake J, Ball G, Kerin MJ. MicroRNA signatures predict Estrogen receptor, Progesterone receptor and HER2/neu receptor status in Breast Cancer. Breast Cancer Res. May 11(3):R27 2009. [Epub ahead of print] PMID: 19432961

2: Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg. March 2010.

Dr Aoife Lowery was awarded the MMI CSFP gold medal following presentation of her work during the 2009 Annual Meeting of the MMI Clinician Scientist Fellowship Programme.

For further details on the MMI CSFP, please click here