Research ArticleCancer

The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis–Specific Transcriptional Program in Breast Cancer Cells

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Sci. Signal.  02 Oct 2012:
Vol. 5, Issue 244, pp. ra71
DOI: 10.1126/scisignal.2002962

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Metastatic Route to the Lung

Many individuals with cancer die from secondary tumors or metastases that spread through blood or lymph vessels to other tissues from the primary tumor site. The members of the Rho family of guanosine triphosphatases (GTPases) promote tumor growth and metastasis and are activated by guanine nucleotide exchange factors (GEFs). Rho GEFs are attractive pharmacological targets because they have potentially druggable catalytic activities and more restricted distribution patterns than Rho proteins. Citterio et al. found that the mRNA abundance of the GEFs Vav2 and Vav3 was increased in certain breast cancer subtypes in patient samples. Mice implanted with breast cancer cells in which Vav2 and Vav3 had been silenced developed slowly growing breast tumors and did not develop lung metastases. Vav2- and Vav3-deficient breast cancer cells showed an altered transcriptional profile, leading the authors to further analyze the role of select target genes encoding proteins that could be pharmacologically inhibited, such as the enzyme cyclooxygenase-2. When implanted into mice, breast cancer cells with deficiencies in individual Vav target genes showed defects in proliferation, angiogenesis, the ability to enter or exit blood vessels during metastasis, and the ability to colonize the lung. When applied to human breast cancer data sets, the changes in the abundance of a subset of mRNAs from the Vav transcriptome generated a gene signature that accurately predicted if patients survived and were free of detectable lung metastasis. These results identify possible targets for treating breast cancer and preventing secondary lung metastases and provide a potential prognostic tool for clinicians.