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JCS ePress online publication date 5 Aug 2003
doi: 10.1242/jcs.00725

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Research Article

Suprabasal {alpha}6{beta}4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGF{beta} signalling


David M. Owens, M. Rosario Romero, Clare Gardner, and Fiona M. Watt*
* Author for correspondence (e-mail: fiona.watt{at}cancer.org.uk)

Inappropriate {alpha}6{beta}4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of {alpha}6{beta}4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the {beta}4 cytoplasmic domain. Suprabasal {alpha}6{beta}4 also perturbed transforming growth factor {beta} (TGF{beta}) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal {alpha}6{beta}4 relieved TGF{beta}-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGF{beta} could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal {alpha}6{beta}4 promotes tumourigenesis by preventing TGF{beta} from suppressing clonal expansion of initiated cells in the epidermal basal layer.
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