title: Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis.
abstract: The EGFR family (ErbB2/Her2 and EGFR/ErbB1/Her1) often modulates the transcriptional program involved in promoting mammary tumorigenesis. In humans, the majority of ErbB2-positive sporadic breast cancers harbor p53 mutations, which correlate with poor prognosis. Also, the extremely high incidence of ErbB2-positive breast cancer in women with p53 germline mutations (Li-Fraumeni syndrome) suggests a key role of mutant p53 specifically in ErbB2-mediated mammary tumorigenesis. To examine the role of mutant p53 during ErbB2-mediated mammary tumorigenesis, a mutant p53 allele (R172H) was introduced into the (MMTV)-ErbB2/Neu mouse model system. Interestingly, we show in heterozygous p53 mice that mutant p53 R172H is a more potent activator of ErbB2-mediated mammary tumorigenesis than simple loss of p53. The more aggressive disease in mutant p53 animals was reflected by earlier tumor onset, increased mammary tumor multiplicity, and shorter survival. These in vivo and in vitro data provide mechanistic evidence that mutant p53 amplifies ErbB2 and EGFR signaling to promote the expansion of mammary stem cells and induce cell proliferation.
  
  
  CONCLUSIONS
  This study identifies mutant p53 as an essential player in ErbB2 and EGFR-mediated mammary tumorigenesis and indicates the potential translational importance of targeting mutant p53 in this subset of patients with breast cancer.
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Yallowitz
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Dun
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lobko
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mott
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Alice
authors.initials: A
authors.lastname: Nemajerova
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York. natalia.marchenko@stonybrook.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Marchenko
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse