MicroRNA therapeutics in preclinical cancer models.

www.thelancet.com/oncology Vol 12 April 2011 319 was not a substantial change in KRAS mRNA in KRASvariant triple-negative tumours, Paranjape and colleagues reported an enrichment of both the NRAS mutant and MAP-kinase-activation signatures in tumours that had the polymorphism. Moreover, in line with previous reports in non-small-cell lung cancer, expression of let-7 family members was lower in KRAS variant triple-negative breast cancer than it was in non-KRAS variant cancer. Therefore, KRAS-variant triple-negative breast cancer shows substantial changes in RAS and let-7 pathway activity. These fi ndings provide valuable insights into the relation of let-7 with subtype-specifi c risk of breast cancer. Analyses of this scale and depth raise several important questions. First, what is the role of individual let-7 targets (eg, KRAS, HMGA2, and CMYC) in triplenegative breast cancer? Is there a functional relation between let-7 expression and BRCA1 expression or function, such that reduced concentrations of let-7 can bypass the need for BRCA1 mutation in triple-negative breast cancer? If so, might such an association help with development of therapeutic strategies targeting homologous recombination repair defi ciency? In this regard, does the enrichment of the MAP-kinase activation signature suggest that KRAS-variant triple-negative breast cancer has enhanced signalling through the MAP-kinase pathway or particular sensitivity to MAP-kinase inhibitors? Finally, and perhaps most importantly, the odds ratio for risk of development of triple-negative breast cancer in one cohort of premenopausal women was 2·307 (95% CI 1·261–4·219). Equivalently strong odds ratios were reported for the KRAS variant in a cohort of smokers with non-small cell lung cancer and fewer than 40 pack-years smoking history. Although these studies need validation in independent cohorts, the magnitude of the association of the KRAS-variant and triple-negative breast cancer suggests basic research on miRNA–mRNA target interactions might contribute clinically to risk stratifi cation of premenopausal women within breast-cancer-screening trials.