Editors' ChoiceCancer

RAS signaling unleashed in breast cancer

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Science Signaling  20 Jan 2015:
Vol. 8, Issue 360, pp. ec16
DOI: 10.1126/scisignal.aaa6958

Cancer cells undergo a switch called epithelial-to-mesenchymal transition (EMT) to gain migratory and invasive phenotypes associated with metastasis. Mutations in the guanosine triphosphatase (GTPase) RAS contribute to EMT by disrupting epithelial cell adhesion and polarity. Okada et al. investigated the role of Rho GTPases, members of the RAS superfamily, in breast cancer progression. Bioinformatic analysis of basal-like and triple-negative breast cancers showed that low expression of the gene encoding the Rho GTPase RND1 correlated with a RAS-associated gene signature, MYC expression, metastasis, and poor survival in patients. Knocking down RND1 induced transformation and partial EMT phenotypes in human mammary epithelial MCF10A cells in culture and in mouse ductal-alveolar progenitor Comma-D cells in mice. Ectopic expression of RND1 impaired the ability of ERBB2-transformed mouse 4T1 mammary tumor cells to metastasize to the lung. RND1 loss also induced RAS activation, RAS-target gene expression, and a transient increase in cell cycle progression followed by increased production of ROS (reactive oxygen species) and cellular senescence in MCF10A cells; however, cells with increased abundance of MYC did not exhibit senescence. RND1 binds to and activates the cytoplasmic GAP (GTPase-activating protein) domain of Plexin B1, a co-receptor for semaphorin-4D that mediates axon growth cone collapse. The abundance of semaphorin-4D was increased in breast cancer cells. Similar to the effects of knocking down RND1, knocking down Plexin B1 induced RAS activation and EMT phenotypes in MCF10A cells. Plexin B1 has also GAP activity toward the RAS-related protein RAP1. Loss of RND1 in MCF10A cells activated RAP1, inhibited p120 RAS-GAP activity (consistent with RAP1 activity), and increased GTP loading on RAS. Expression of the genes encoding RND1, Plexin B1, and p120 RAS-GAP was decreased in nonoverlapping subsets of basal-like breast cancers. Together the findings reveal mechanisms of altered RAS regulation that induces EMT and metastasis in basal-like breast cancers.

T. Okada, S. Sinha, I. Esposito, G. Schiavon, M. A. López-Lago, W. Su, C. A. Pratilas, C. Abele, J. M. Hernandez, M. Ohara, M. Okada, A. Viale, A. Heguy, N. D. Socci, A. Sapino, V. E. Seshan, S. Long, G. Inghirami, N. Rosen, and F. G. Giancotti, The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling. Nat. Cell Biol. 17, 81–94 (2015). [PubMed]

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