Molecular Medicine Select

Much progress has been made in identifying the factors that cause tumor formation. Yet, how cancer cells leave primary tumors to colonize distant organs—a process called metastasis—is still poorly understood. Here we discuss recent advances that describe factors that promote the invasive ability of cancer cells. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, both normal (such as development) and abnormal (such as tumor formation). Now, Ma et al. (2007) reveal that miRNAs also promote the metas-tasis of cancer cells. They examined 29 miRNAs known to have altered expression in primary breast carcinomas compared with normal mammary tissue and homed in on miR-10b because it is highly expressed in certain meta-static breast cancer cells. Remarkably, silencing of this miRNA reduced the ability of the breast cancer cells to undergo one of the hallmarks of metastasis—invasion through an artificial matrix; in contrast, overexpression of miR-10b increased the motility and invasiveness of these cells. To analyze miR-10b's effects on metastasis in vivo, Ma et al. overexpressed miR-10b in nonmetastatic human breast cancer cells and implanted these cells into the mammary fat pads of immunodeficient mice. Unlike the control nonmetastatic human breast cancer cells that formed noninvasive tumors, the cells overexpressing miR-10b invaded the stroma, muscles, and vasculature and were able to metastasize to distant sites such as the lung. This metastatic switch involves some of the same transcription factors that control the epithelial-to-mesenchymal transition (EMT) during development. Ma et al. observed that ectopic expression of the EMT-promoting transcription factor Twist increased the amount of miR-10b in human mammary epithelial cells. This effect is probably direct as Twist binds to the promoter of miR-10b. Silencing of miR-10b in cells overexpressing Twist reduced the mobility and invasiveness of these cells. To identify the mRNA targets of miR-10b, Ma et al. used a computational strategy. This approach identified HOXD10 mRNA (HOXD10 is known to suppress expression of genes involved in cell migration and in remodeling of the extracellular matrix) as a potential target of miR-10b. Overexpression of miR-10b reduced the amount of HOXD10 protein and caused increased expression of the gene RHOC, which is well-known to be important in metastasis and is repressed by HOXD10. To determine whether miR-10b expression correlates with clinical outcome, Ma et al. analyzed primary tumor samples from patients with breast cancer. Interestingly, 50% of patients with metastatic breast cancer had increased expression of miR-10b in their primary …