Transcriptional alterations in neoplastic transformation

Genetic alterations aberrantly turn on oncogenic transcription programs, thereby driving cellular transformation and tumor progression. Transcription comprises multiple steps, including initiation, promoter-proximal pausing, pause release, elongation, and termination. Because these steps are essential in both normal and cancer cells, targeting transcription has historically lacked therapeutic specificity. To address this problem, a key unmet need for the field is to identify differential features of transcription between normal and transformed cells to then exploit factors that regulate those distinctions. In line with this goal, we have identified two distinct changes in global transcription dynamics in normal breast cells undergoing oncogenic transformation. First, oncogenic transformation is associated with global increases in transcription elongation rate, or the speed by which RNA Polymerase II (Pol II) travels in gene bodies. This heightened rate is not just observed at genes inducible upon transformation, suggesting that oncogenic signaling may exploit elongation control to globally alter the transcriptome to advance cellular transformation. Second, oncogenic transformation is associated with decreases in promoter proximal pausing, implying that one of two potential mechanisms is elicited once cells undergo this cell state change: (i) increased premature termination to evict Pol II off promoters, and/or (ii) decreased Pol II recruitment. Given these findings, I hypothesize that oncogenic transformation requires global alterations to multiple transcription steps, and that perturbation of factors that selectively regulate these steps may obstruct the transformation process without killing normal cells, enabling the identification of targetable therapeutic approaches.