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 2

RASAL2 overexpression is associated with poor disease outcome, metastasis, and tumor recurrence in TNBC or ER-negative tumors.

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RASAL2 overexpression is associated with poor disease outcome, metastasi...
(A and B) Kaplan-Meier analyses of overall survival and early distance metastasis combined with relapse-free survival (DMFS & RFS), respectively, using the GOBO database. Patients were stratified according PAM50 subtypes as indicated. (C) Similar analysis as in A and B, but patients were stratified according ER status as indicated. (D) Multivariate analysis of ER-negative tumors in the patients in C. (E) IHC staining of RASAL2 on primary tumors and matched node metastasis specimens from 2 representative patients as well as the relative RASAL2 expression in metastatic tumors relative to that in paired primary tumors in a TMA comprising 25 ER-negative and 11 ER-positive patients. ER positivity was determined by IHC using 5% ER-positive cells as a cutoff point. Data were analyzed using a paired 2-tailed t-test and are reported as mean ± SEM. Scale bar: 100 μm. (F) qPCR analysis of RASAL2 mRNA expression levels in a group of paired primary and recurrent TNBC tumors (n = 8). Blue dots represent individual primary tumors, red dots represent recurrent tumors after surgery and chemotherapy, and dotted lines connect data from individual patients. (G) Stratified analysis of data from Esserman (ref. 29; GEO accession no. GSE22226), correlating RASAL2 levels with 5-year (recur at 5Y) recurrence incidence in ER-positive or ER-negative groups of patients. NR, no recurrence.