title: A mouse model with T58A mutations in Myc reduces the dependence on KRas mutations and has similarities to claudin-low human breast cancer.
abstract: Expression of c-Myc is highly prevalent in human breast cancer and stability of the oncoprotein is regulated through Ras-regulated phosphorylation at serine 62 and threonine 58. Previous studies have illustrated the importance of accumulation of KRas mutations in Myc-mediated tumor formation. To examine Myc dependence upon Ras mutations we have generated MMTV regulated Myc and Myc T58A transgenic mice. Expression of the more stable T58A Myc allele resulted in a reduction in KRas-activating mutations. However, in a low-level expression T58A Myc transgenic, the majority of the tumors were squamous or epithelial-to-mesenchymal in nature and accumulated KRas mutations at a higher frequency. Interestingly, we show that these mice develop similar gene expression patterns and signaling pathway utilization as a subtype of human claudin-low breast cancer. Indeed, our results demonstrate a clear division in human claudin-low tumors based on Myc pathway activation and target genes. Together, our results demonstrate that Myc expression and stability has critical effects on molecular heterogeneity in mouse mammary tumors that parallel subtypes of human breast cancer.
authors.affiliation: Department Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Hollern
authors.forename: I
authors.initials: I
authors.lastname: Yuwanita
authors.forename: E R
authors.initials: ER
authors.lastname: Andrechek
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D057167:Claudins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction
chemical_list: D057167:Claudins