RASAL2 activates RAC1 to promote triple-negative breast cancer progression
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
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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Research Article Oncology

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 4

Role of RASAL2 in TNBC metastasis in vivo.

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Role of RASAL2 in TNBC metastasis in vivo. (A) Schematic of ex vivo anal...
(A) Schematic of ex vivo analysis of parental 4T1 cells and a lung metastatic subline (4T1-LM). Original magnification, ×100. (B) qPCR analysis of miR-203, RASAL2 mRNA, and protein levels of indicated cells. (C) Primary tumor size after orthotopic injection of mammary fat pads with 4T1 control cells (Vector) and 4T1 cells expressing ectopic RASAL2 as well as RASAL2 Western blot. (D) The number of lung metastasis nodules from spontaneous metastasis after orthotopic injection of 4T1 cells and an image of whole lung 4 weeks after injection. (E) Representative bioluminescence (BLI) images of female NOD/SCID mice showing the primary tumors at week 4 derived from orthotopic injection of MB231-LN control cells (NC) and RASAL2 deleted cells by shRNA (KD) and quantification of the primary tumor (n = 16). (F) Representative bioluminescence images of female NOD/SCID mice showing both the primary tumors (hind leg) and metastasis (lung) derived from orthotopic injection of MB231-LN cells with control and RASAL2 KD treatment at week 8. Quantification of the pulmonary metastases by bioluminescence measurement (n = 16). (G) Kaplan-Meier curves of mice from E and F (n = 16). Curves were compared using a log-rank (Mantel-Cox) test. P = 0.008. (H) Representative bioluminescence images of lung metastasis development in female NOD/SCID mice injected via lateral tail vein with control and RASAL2 KD cells and quantification of pulmonary metastases by bioluminescence measurement (n = 16). (I) Kaplan-Meier curves of mice from H (n = 16). Curves were compared using a log-rank (Mantel-Cox) test. P = 0.019.