Prognostic signatures in breast cancer: correlation does not imply causation

Breast cancer encompasses a plethora of distinct diseases characterised by different biological features and clinical outcomes [1-3]. Microarray-based gene expression profiling studies have played a pivotal role in unravelling the molecular and clinical diversity of the disease (for a review see [3]). These studies led to the development of a molecular classification of breast cancer [4], where the different molecular subtypes identified were found to be associated with distinct clinical outcomes [5,6], and to the development of numerous multigene predictors (that is, gene signatures) of outcome, which were initially reported to outperform the current clinicopathological algorithms to define the prognosis of breast cancer patients [7,8] (reviewed in [3,9]).Microarrays have also played a pivotal role in addressing one of the major bottlenecks in translational research: ascribing relevance in the human disease context of results obtained from in vitro studies and animal models. The availability of multiple gene expression datasets with patient follow-up in the public domain allowed the investigation of whether a microarray-based signature derived from a set of laboratory experiments would have biological significance. For instance, a signature derived from tumour-initiating breast cancer cells was shown to be of prognostic significance in a publicly available microarray dataset, and this was used as the basis to suggest that the tumourigenic breast cancer cell signature 'may detect transcriptional profiles associated with mutations that arrest cells in an immature state of differentiation and function as markers of more aggressive tumors' [10].In their recent paper [11], Venet and colleagues made the intriguing observation that gene signatures developed to identify phenomena completely unrelated to cancer - such as the effect of postprandial laughter on peripheral blood mononuclear cells, the localisation of skin fibro-blasts or social defeat obtained from mice brains