Xiaoli Zhang


July 2011

Document Type


Degree Name



Dept. of Molecular and Medical Genetics


Oregon Health & Science University


Overexpression of the c-Myc transcription factor occurs in the majority of human breast cancer. Gene amplification and increased transcription are only found in a subset of those with overexpression of c-Myc protein. How c-Myc overexpression occurs in the rest of human breast cancer is still not clear. This thesis seeks to investigate the possibility and mechanisms of increased c-Myc protein stability contributing to its overexpression in breast cancer. c-Myc protein stability is regulated by a signaling pathway that controls phosphorylation events on the two conserved amino acids: Serine 62 and Threonine 58. Phosphorylation of the two amino acids has opposite roles on c-Myc protein stability. Phosphorylation of Serine 62 stabilizes while phosphorylation of Threonine 58 destabilizes c-Myc and this requires prior phosphorylation at Serine 62. Here I show that c-Myc protein stability is increased in breast cancer cell lines and is associated with increased phosphorylation at Serine 62 and decreased phosphorylation at Threonine 58. Moreover, this shift of phosphorylation of Serine 62 and Threonine 58 levels also occurs in primary human breast cancer. Thus increased c-Myc protein stability is a new mechanism of c-Myc overexpression in human breast cancer. To test the underlying mechanisms of increased c-Myc protein stability, I have focused on two proteins, the tumor suppressor Axin1 and the oncoprotein HER2. Axin1 is a scaffold protein that coordinates a destruction complex for c-Myc. My study show that deregulation of Axin1, including decreased total level of Axin1 and a preferred expression of an Axin1 splice variant, Axin1v2, correlates with deregulation of c-Myc degradation in breast cancer. Axin1v2, unlike the other Axin1 splice variant, Axin1v1, is not able to promote c-Myc dephosphorylation at S62, nor is it able to inhibit c-Myc activity. Knocking down of Axin1 in non-transformed cells increases, while increasing Axin1 expression in cancer cell lines inhibits c-Myc's oncogenic activity. Thus, these results identify deregulation of Axin1 as a new mechanism of deregulating c-Myc in human breast cancer. To explore other mechanisms that lead to deregulation of c-Myc, I examined c-Myc regulation by the Tyrosine kinase receptor HER2, which is overexpressed in 25-30% of human breast cancer. Activation of HER2 can lead to activation of the two key pathways that control phosphorylation of c-Myc at Serine 62, Ras-MAPK and PI(3)K-Akt. Here I show that activation of HER2 increases c-Myc protein stability, phosphorylation at Serine 62 and DNA binding at c-Myc target gene promoters, while inhibiting HER2 does the opposite. Thus, overexpression of HER2 can be another way of deregulating c-Myc in human breast cancer. Taken together, these results provide mechanistic insight into how c-Myc protein stability can be deregulated in human breast cancer. Understanding whether and how deregulation of c-Myc protein stability occurs in human cancer is critical for developing Myc-targeted therapies.




School of Medicine



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