Reduced proliferation and enhanced migration: Two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1

Hyperproliferation induced by various oncogenic proteins, including activated Ras, is the most prominent and well characterized feature of cancerous cells. This property has been exploited in the development of the most successful anti-cancer treatments to target rapidly dividing cells. Here we argue that hyperproliferation may in fact be detrimental to survival during particular stages of cancer progression such as dissemination from primary tumors and establishment of metastatic outgrowth. Our recent work has demonstrated that elevation of YB-1 protein levels, which is frequently observed in human cancers, is associated with reduced proliferation rates in disseminated mesenchymal-like breast carcinoma cells. In breast cancer cell lines with activated Ras-MAPK signaling, YB-1 inhibited cellular proliferation, while inducing an epithelial-to-mesenchymal transition (EMT). The underlying mechanism involves YB-1-mediated translational repression of pro-growth transcripts and activation of messages encoding EMT-associated proteins, many of which are also known to inhibit proliferation. In addition to their lack of polarity and increased mobility and invasiveness, YB-1-overexpressing cells displayed a remarkable ability to shut down proliferation and survive in anchorage-independent conditions. These findings support the view that while an increase in proliferation is important for the initiation and maintenance of primary tumors, growth inhibition could ultimately be crucial for survival of carcinoma cells in the circulation and secondary organs, thereby leading to the development of a more malignant phenotype.