Conditional expression of the ErbB2 oncogene elicits reversible hyperplasia in stratified epithelia and up-regulation of TGFα expression in transgenic mice

Abstract

The ErbB2 receptor tyrosine kinase (RTK) is expressed in basal cells of squamous epithelia and the outer root sheath of hair follicles. We previously showed that constitutive expression of activated ErbB2 directed to these sites in the skin by the keratin 14 (K14) promoter produces prominent hair follicle abnormalities and striking skin hyperplasia in transgenic mice. However, perinatal lethality precluded the establishment of a transgenic line for analysis of ErbB2 function in adult animals. To investigate the signi®cance of ErbB2 signaling in epithelial tissues during and post development, we developed a K14-rtTA/TetRE-ErbB2`Tet-On' bitransgenic mouse system. These mice were normal until the ErbB2 transgene was induced by exposure to doxycycline (Dox). Prenatal induction resulted in perinatal death. Postnatally, ErbB2 transgene expression was observed at 4 h after the initiation of Dox, and reached a plateau at 24 h. Skin hyperplasia followed after 2 days and these changes reverted to normal upon Dox withdrawal. In adults, as in the neonates, prolonged ErbB2 induction caused prominent skin and hair follicle hyperplasias. Severe hyperplasias in the cornea, eye lids, tongue and esophagus were also observed. ErbB2 transgene induction was accompanied by increased expression of TGFa, a ligand of epidermal growth factor receptor (EGFR), and to a lesser extent, EGFR, further enhancing RTK signal transduction. We conclude that ErbB2 plays important roles in both development and maintenance of hair follicles and diverse squamous epithelia and that this ligand-inducible and tissue-speci®c Tet-On' transgenic mouse system provides a means to study transgenes with perinatal toxicity.

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…This has also been corroborated in a tet-inducible transgenic models. Tetracycline-induced expression of activated HER2 in squamous epithelia of mice results in severe hyperplastic abnormalities of squamous epithelial tissues, which reverse upon withdrawal of the HER2 transgene expression (Xie et al, 1999). Tumors in MMTV-neuT mice are also dependent on continued oncogene expression.…”

Mouse genetics in cell biology

“…The ability to achieve reversible transgene expression with the rtTA system has allowed an oncogene to be expressed in a reversible manner to perturb cell-cell and cellextracellular matrix interactions. Thus, several mouse models in which the appearance, the maintenance and the regression of skin tumours could be regulated with doxycycline were created Xie et al 1999). In one of these models, a dominant-active form of the oncoprotein H-Ras, H-RasV12G, was expressed in melanocytes under the control of the rtTA system in mice carrying a null mutation in the tumour suppressor INK4a gene.…”

“…This indicated that the appearance and maintenance of melanomas is strictly dependent on H-Ras expression and that the activation of H-Ras and the loss of INK4a seem to cooperate for the development of melanomas in a reversible manner. Similarly in a second mouse model, skin hyperplasia could be reversibly induced by doxycycline-dependent expression of an active form of the ErbB2 receptor tyrosine kinase under the control of the keratin 14 promoter using the rtTA system (Xie et al 1999). These in vivo models provide novel insight into the role of H-ras and ErbB2 in homotypic and heterotypic interactions between host and tumour cells underlying the formation and the maintenance of tumours.…”

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations part B. Transgenic mouse models

“…ErbB2 transgene expression was observed after the administration of doxycycline. 12 In adult transgenic mice, severe hyperplasias were noted in the skin, cornea, eyelids, tongue and esophagus. These were accompanied by increased expression of TGF-a, a ligand of the epidermal growth factor receptor.…”

“…Xie et al (1999) developed a k14-rTA/TetRE-ErbB2 ÔTet-onÕ bitransgenic mouse system to investigate the significance of ErbB2 signaling in epithelial tissues. These mice were normal until the ErbB2 transgene was induced by exposure to doxycycline (Dox).…”