Figure 2

Aberrant Myc expression causes mammary cancer. Myc is deregulated in most mammary tumors by multiple mechanisms, including gene amplification, or aberrant expression due to alterations in signaling pathways that influence Myc RNA or protein levels as well as its transcriptional activity. Each of the indicated proteins or pathways impacts on Myc expression or activity in mammary cancer. Specifically, the Notch and Wnt pathway effectors, Notch intracellular domain/C promoter-binding factor 1 and β-catenin/T-cell factor, respectively, as well as estrogen receptor alpha (ERα), bind the Myc promoter, thereby stimulating transcription. Dysregulation of transforming growth factor beta (TGFβ) and Brca1 in mammary cancer has been reviewed recently [34]. TGFβ, via Smads, suppresses Myc expression, while Brca1, which is frequently deregulated in ERα-negative, basal-like breast cancer, normally blocks Myc transcriptional activity. The ubiquitin-specific protease ubiquitin-specific protease 28 (USP28) was found overexpressed in breast tumors [38] and stabilizes Myc via antagonizing F-box and WB repeat domain containing 7 (FBW7), which is frequently lost or mutated in breast tumors [37]. Finally, ErbB2 activation, which is also regulated by ERα, stimulates pathways like rat sarcoma/extracellular signal-related kinase (Ras/Erk) and phosphoinositide 3-kinase/serine/threonine kinase Akt (PI3K/Akt) that influence Myc RNA and protein levels. See text for further details. Myc is an activator of RNA polymerase II-driven transcription for multiple target genes [2] and also affects RNA polymerase I- and III-mediated transcription, thus regulating ribosome biogenesis and translation. In cancer cells, the outcome of deregulated Myc will be wide-ranging considering that Myc influences the cell cycle, protein synthesis, cell growth and metabolism, cell death, genomic instability, tumor-induced angiogenesis, adhesion, as well as other cellular functions. This is exemplified by examining the effects of Myc knockdown in breast cancer cell lines, where a genomic and phenotypic analysis revealed that selectively regulated target genes in each cell line were responsible for the differential effects resulting from Myc loss [40].