Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice.

overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when is overexpressed, we created a mouse model that expresses high levels of in all tissues. Phenotypic characterization of these mice revealed over-branching of the mammary glands in females. Transcriptomic analyses indicate the upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the -overexpressing mice, including estrogen receptor, ERK/MAPK, and TGFβ signaling. However, overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of are not sufficient to induce tumors, but it may enhance signaling abnormalities associated with oncogenesis.