Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours

Proteins of the Rho family control signalling pathways that regulate the actin cytoskeleton and gene transcription1,2. In vitro studies have implicated Rho-like GTP-hydrolysing enzymes

(GTPases) in cell migration3,4,5, cell-cycle progression6,7, and Ras-induced focus formation8,9, suggesting a role for these GTPases in the formation and progression of tumours in vivo. To

study this, we have generated mice lacking the Rac-specific activator Tiam110,11,12, a T-lymphoma invasion and metastasis inducing protein. Here we show that such Tiam1-/- mice are resistant

to the development of Ras-induced skin tumours initiated with 7,12-dimethylbenzanthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate. Moreover, the few tumours produced in

Tiam1-/- mice grew much slower than did tumours in wild-type mice. Tiam1-deficient primary embryonic fibroblasts were also resistant to RasV12-induced focus formation. Analysis of Tiam1

heterozygotes indicated that both tumour initiation and promotion were dependent on the Tiam1 gene dose. Tiam1 deficiency was associated with increased apoptosis during initiation, and with

impeded proliferation during promotion. Although the number of tumours in Tiam1-/- mice was small, a greater proportion progressed to malignancy, suggesting that Tiam1 deficiency promotes

malignant conversion. Our studies identify the Rac activator Tiam1 as a critical regulator of different aspects of Ras-induced tumour formation.

We thank J.-Y. Song and the Animal Pathology department of the Netherlands Cancer Institute for histological analysis; D. Stuart, P. Demant and A. Hurlstone for advice; P. Krimpenfort and T.

Schrauwers for experimental support; V. Zoumbourlis and A. Balmain for cell lines; and the animal facility of the Netherlands Cancer Institute for providing animal care. Part of this work

was supported by the Dutch Cancer Society, the European Community, and the Association for International Cancer Research.

Present address: Galapagos Genomics, Archimedesweg 4, 2333 CN, Leiden, The Netherlands

Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Angeliki Malliri, Rob A. van der Kammen, Kristopher Clark, Maarten van der Valk & John G. Collard

The authors declare that they have no competing financial interests.

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