Fig. 7. Differential 5′UTR utilization facilitates breast cancer plasticity.

A diagram of a working model demonstrating how the expression of multiple mRNAs sharing the same coding sequence but differing in their 5′UTR sequences can facilitate adaptation to insult—hypoxia, or mTORi. Though simplified, in response to stress mRNAs fall into three broad categories: Those whose translational efficiency is decreased in response to stress—mTOR sensitive 5′UTRs; those with unaltered expression against a background of translational repression—non-stress-inducible 5′UTRs; and those translationally upregulated during stress—stress-inducible ATF4-like 5′UTRs. Alterations in the balance of expression resulting from this translational switch transition cells from a proliferative chemosensitive state to a plastic chemoresistant state. ISRIB blocks selective translation mediated by the induction of ISR, reducing the pro-survival plastic effects of the selectively translated mRNA.