RASAL2 Activates RAC1 to Promote Triple-negative Breast Cancer Progression

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2014 Nov 11

PMID 25384218

Citations 55

Authors

Min Feng

Yi Bao

Zhimei Li

Juntao Li

Min Gong

Stella Lam

Jinhua Wang

Diego M Marzese

Nicholas Donovan

Ern Yu Tan

Dave S B Hoon

Qiang Yu

Affiliations

Soon will be listed here.

Abstract

Patients with triple-negative breast cancer (TNBC) have a high incidence of early relapse and metastasis; however, the molecular basis for recurrence in these individuals remains poorly understood. Here, we demonstrate that RASAL2, which encodes a RAS-GTPase-activating protein (RAS-GAP), is a functional target of anti-invasive microRNA-203 and is overexpressed in a subset of triple-negative or estrogen receptor-negative (ER-negative) breast tumors. As opposed to luminal B ER-positive breast cancers, in which RASAL2 has been shown to act as a RAS-GAP tumor suppressor, we found that RASAL2 is oncogenic in TNBC and drives mesenchymal invasion and metastasis. Moreover, high RASAL2 expression was predictive of poor disease outcomes in patients with TNBC. RASAL2 acted independently of its RAS-GAP catalytic activity in TNBC; however, RASAL2 promoted small GTPase RAC1 signaling, which promotes mesenchymal invasion, through binding and antagonizing the RAC1-GAP protein ARHGAP24. Together, these results indicate that activation of a RASAL2/ARHGAP24/RAC1 module contributes to TNBC tumorigenesis and identify a context-dependent role of RASAL2 in breast cancer.

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References

Joyce J, Pollard J . Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009; 9(4):239-52. PMC: 3251309. DOI: 10.1038/nrc2618. View

Burridge K, Wennerberg K . Rho and Rac take center stage. Cell. 2004; 116(2):167-79. DOI: 10.1016/s0092-8674(04)00003-0. View

Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A . Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene. 2007; 26(54):7590-5. DOI: 10.1038/sj.onc.1210564. View

Symons M, Segall J . Rac and Rho driving tumor invasion: who's at the wheel?. Genome Biol. 2009; 10(3):213. PMC: 2690992. DOI: 10.1186/gb-2009-10-3-213. View

Chaffer C, Weinberg R . A perspective on cancer cell metastasis. Science. 2011; 331(6024):1559-64. DOI: 10.1126/science.1203543. View

Sosa M, Lopez-Haber C, Yang C, Wang H, Lemmon M, Busillo J . Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell. 2010; 40(6):877-92. PMC: 3038344. DOI: 10.1016/j.molcel.2010.11.029. View

Cao Q, Mani R, Ateeq B, Dhanasekaran S, Asangani I, Prensner J . Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011; 20(2):187-99. PMC: 3157014. DOI: 10.1016/j.ccr.2011.06.016. View

Foulkes W, Smith I, Reis-Filho J . Triple-negative breast cancer. N Engl J Med. 2010; 363(20):1938-48. DOI: 10.1056/NEJMra1001389. View

Bloomston M, Frankel W, Petrocca F, Volinia S, Alder H, Hagan J . MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007; 297(17):1901-8. DOI: 10.1001/jama.297.17.1901. View

10.

Spano D, Heck C, De Antonellis P, Christofori G, Zollo M . Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012; 22(3):234-49. DOI: 10.1016/j.semcancer.2012.03.006. View

11.

Citterio C, Menacho-Marquez M, Garcia-Escudero R, Larive R, Barreiro O, Sanchez-Madrid F . The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. Sci Signal. 2012; 5(244):ra71. DOI: 10.1126/scisignal.2002962. View

12.

Png K, Halberg N, Yoshida M, Tavazoie S . A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2011; 481(7380):190-4. DOI: 10.1038/nature10661. View

13.

Rhodes D, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs B . Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2):166-80. PMC: 1813932. DOI: 10.1593/neo.07112. View

14.

Perou C, Sorlie T, Eisen M, van de Rijn M, Jeffrey S, Rees C . Molecular portraits of human breast tumours. Nature. 2000; 406(6797):747-52. DOI: 10.1038/35021093. View

15.

Visone R, Russo L, Pallante P, De Martino I, Ferraro A, Leone V . MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr Relat Cancer. 2007; 14(3):791-8. DOI: 10.1677/ERC-07-0129. View

16.

Ma L, Teruya-Feldstein J, Weinberg R . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007; 449(7163):682-8. DOI: 10.1038/nature06174. View

17.

Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y . miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol. 2013; 15(3):284-94. PMC: 3672398. DOI: 10.1038/ncb2690. View

18.

Korpal M, Lee E, Hu G, Kang Y . The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008; 283(22):14910-4. PMC: 3258899. DOI: 10.1074/jbc.C800074200. View

19.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

20.

Iorio M, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P . MicroRNA signatures in human ovarian cancer. Cancer Res. 2007; 67(18):8699-707. DOI: 10.1158/0008-5472.CAN-07-1936. View