title: Interaction between MYC and MCL1 in the genesis and outcome of non-small-cell lung cancer.
abstract: MYC exerts both positive and negative functions in cancer cells, such that its procancerous effects are unmasked only after its anticancer effects are blocked. Here we used multiple mouse models of lung adenocarcinoma to identify genetic events that can cooperate with MYC activation to promote the genesis of non-small-cell lung cancer (NSCLC), the most common form of lung cancer in humans. MYC overexpression targeted to pulmonary alveolar cells was sufficient to induce lung adenomas and carcinomas. Tumorigenesis was assisted by either spontaneous mutations in Kras or experimental introduction of activated RAS, but investigations revealed that additional events were required to circumvent apoptosis, one of the most significant negative functions exerted by MYC. We determined that overexpression of the antiapoptotic protein MCL1 was sufficient to circumvent apoptosis in this setting. Previous clinical studies have indicated that prognosis of human NSCLC is not associated with MCL1, despite its overexpression in many NSCLCs. In reexamining the prognostic value in this setting, we found that MCL1 overexpression does correlate with poor patient survival, but only when accompanied by MYC overexpression. Our findings therefore produce a convergence of mouse and human results that explain how MCL1 can block an important negative consequence of MYC overexpression in both experimental models and clinical cases of NSCLC.
authors.affiliation: G.W. Hooper Research Foundation, University of California, San Francisco, USA. Thaddeus.Allen@ucsf.edu
authors.forename: Thaddeus D
authors.initials: TD
authors.lastname: Allen
authors.forename: Chang Qi
authors.initials: CQ
authors.lastname: Zhu
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: Naoki
authors.initials: N
authors.lastname: Yanagawa
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bishop
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D018631:ras Proteins