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Oncogenic Activating Mutations in the neu/erbB ‐2 Oncogene Are Involved in the Induction of Mammary Tumors
Author(s) -
CHAN RICHARD,
MULLER WILLIAM J.,
SIEGEL PETER M.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb08722.x
Subject(s) - biology , carcinogenesis , transgene , point mutation , transmembrane protein , transmembrane domain , mutation , mutant , oncogene , cancer research , somatic cell , gene , microbiology and biotechnology , genetics , receptor , cell cycle
Amplification and overexpression of erbB ‐2/ neu is an important determinant in the initiation and progression of human breast cancer. Indeed, transgenic mice that overexpress the neu proto‐oncogene heritably develop mammary adenocarcinomas. Tumorigenesis in these transgenic strains is associated with activation of the intrinsic catalytic activity of Neu. In many of these tumors, activation of Neu occurs as a result of somatic mutations located within the transgene itself. Examination of the altered neu transcripts revealed the presence of in‐frame deletions that encode aberrant Neu receptors lacking 5 to 12 amino acids within the extracellular domain proximal to the transmembrane region of Neu. In addition to these deletion mutants we have also detected single point mutations within this juxtatransmembrane region. The majority of the mutations analyzed affect the one of several conserved cysteine residues present within this region. Introduction of these activating mutations into the wild‐type neu cDNA results in its oncogenic conversion. Taken together, these observations suggest that this cysteine‐rich region plays an important role in regulating the catalytic activity of Neu.