Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion.
The protooncogene c-myc regulates cell growth, differentiation, and apoptosis, and its aberrant expression is frequently observed in human cancer. However, the consequences of activating c-Myc in an adult tissue, in which these cellular processes are part of normal homeostasis, remain unknown. In order to achieve this, we have targeted expression of a switchable form of the c-Myc protein to the skin epidermis, a well characterized homeostatic tissue. We show that activation of c-MycER in adult suprabasal epidermis rapidly triggers proliferation and disrupts differentiation of postmitotic keratinocytes. Sustained activation of c-Myc is sufficient to induce papillomatosis together with angiogenesis--changes that resemble hyperplastic actinic keratosis, a commonly observed human precancerous epithelial lesion. All these premalignant changes spontaneously regress upon deactivation of c-MycER.
Pelengaris
S
S
Imperial Cancer Research Fund, London, United Kingdom. s.pelengaris@icrf.icnet.uk
Littlewood
T
T
Khan
M
M
Elia
G
G
Evan
G
G
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004817:Epidermis / Q000737:chemistry / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018859:Hair Follicle / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010212:Papilloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D004965:Estrogen Antagonists; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; C016601:afimoxifene