Mediator is a conserved, multi-subunit macromolecular machine divided 
structurally into head, middle, and tail modules, along with a transiently 
associating kinase module. Mediator functions as an integrator of 
transcriptional regulatory activity by interacting with DNA-bound transcription 
factors and with RNA polymerase II (Pol II) to both activate and repress gene 
expression. Mediator has been shown to affect multiple steps in transcription, 
including chromatin looping between enhancers and promoters, pre-initiation 
complex formation, transcriptional elongation, and mRNA splicing. Individual 
Mediator subunits participate in regulation of gene expression by the estrogen 
and androgen receptors and are altered in a number of endocrine cancers, 
including breast and prostate cancer. In addition to its role in genomic 
signaling, MED12 has been implicated in non-genomic signaling by interacting 
with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural 
studies have revealed extensive inter-domain interactions and complex 
architecture of the Mediator-Pol II complex, suggesting that Mediator is capable 
of reorganizing its conformation and composition to fit cellular needs. We 
propose that alterations in Mediator subunit expression that occur in various 
cancers could impact the organization and function of Mediator, resulting in 
changes in gene expression that promote malignancy. A better understanding of 
the role of Mediator in cancer could reveal new approaches to the diagnosis and 
treatment of Mediator-dependent endocrine cancers, especially in settings of 
therapy resistance.