RASAL2 activates RAC1 to promote triple-negative breast cancer progression
Min Feng, … , Dave S.B. Hoon, Qiang Yu
Min Feng, … , Dave S.B. Hoon, Qiang Yu
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5291-5304. https://doi.org/10.1172/JCI76711.
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RASAL2 activates RAC1 to promote triple-negative breast cancer progression

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.

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

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Figure 3

RASAL2 knockdown inhibits TNBC invasion and aggressive growth.

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RASAL2 knockdown inhibits TNBC invasion and aggressive growth. (A) Effec...
(A) Effects of 2 independent RASAL2 siRNAs on cell invasion, RASAL2 protein expression levels, and monolayer cell proliferation. (B) Invasion assay and RASAL2 protein levels in cells expressing ectopic RASAL2 treated with a siRNA targeting the 3′ UTR of RASAL2. (C) Wound healing assay of a confluent culture of indicated MB231-LN cells at hour 0 of wound scratching and 6 hours after scratching on collagen I–coated plates. (D) Representative images of cell growth in 3D Matrigel. MB231-LN cell lines were treated as indicated. (E) Representative images and quantification of the number of tumorspheres formed per 100 MB231-LN cells as indicated. (F) Representative images and quantification of CD44hiCD24lo cells in MB231-LN cells treated as indicated. (G) Invasion assay and RASAL2 protein levels in cells expressing ectopic wild type, GAP activity–deficient mutant (GAP-mut), or GAP domain deletion mutant (ΔGAP) RASAL2 treated with a siRNA targeting the 3′ UTR of RASAL2. The data shown represent mean ± SEM of 3 independent or replicate experiments. Original magnification, ×100 (C); ×40 (D and E). *P < 0.05, **P < 0.01, ***P < 0.001.