Tiam1-deficiency impairs mammary tumor formation in MMTV-c-neu but not in MMTV-c-myc mice.
BACKGROUND
Rho-like small GTPases, including RhoA, Rac1 and Cdc42, are crucial for the regulation of a large variety of biological processes such as the cytoskeletal organization and gene transcription. The activities of Rho GTPases are predominantly controlled by guanine nucleotide exchange factors (GEFs), which activate GTPases by catalyzing the exchange of bound GDP for GTP. Earlier, we have identified the Tiam1 gene as an invasion-inducing gene that encodes a specific activator (GEF) of the Rac GTPase. We found that Tiam1-mediated Rac signaling functions in various aspects of tumorigenicity including the formation and progression of Ras-induced skin tumors and Wnt-induced intestinal tumors. Here, we further distinguish the oncogenic pathways that depend on Tiam1 signaling in the mammary gland.


METHODS
We crossed Tiam1 knockout mice with MMTV-c-myc and MMTV-c-neu transgenic mice, in which the expression of both oncogenes is targeted to the mammary gland leading to mammary tumorigenesis.


RESULTS
We found Tiam1 important for Neu-induced tumor formation and progression but not for Myc-induced tumors. Tiam1-deficiency delayed Neu-induced tumor initiation and reduced metastasis but had no effect on the growth of the MMTV-c-neu tumors.


CONCLUSIONS
Our data indicate that the Rac activator Tiam1 contributes to tumorigenicity induced by specific oncogenic signaling pathways only.
Strumane
K
K
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Rygiel
T
T
van der Valk
M
M
Collard
J G
JG
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015996:Survival Rate; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1
D020662:Guanine Nucleotide Exchange Factors; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C489428:Myc protein, mouse; C513260:Tiam1 protein, mouse