Phosphorylated Rasal2 facilitates breast cancer progression

BACKGROUND: Rasal2 has diametric effects on progression of oestrogen receptor-positive (ER+) and -negative (ER–) breast cancers. The relevant causes are unknown. It is also unknown whether the effects of Rasal2 are mediated by an exosome-transport process. METHODS: Exosomes were purified from breast cancer cells and identified by transmission electron microscopy and flow cytometry analysis. In vivo and in vitro experiments were conducted to investigate the role of Rasal2 in exosome-mediated breast cancer progression. Western blot analysis was performed to detect Rasal2 and p-Rasal2 (phosphorylated Rasal2) expression in ER+/ER− breast cancer cells and in exosomes, cancer tissues and blood of patients with ER+ or ER− breast cancer. FINDINGS: Phosphorylation of Rasal2 at Serine 237 promoted tumour growth in both ER+ and ER− tumour cells and tissues. The functions of both p-Rasal2 and non-p-Rasal2 (non-phosphorylated-Rasal2) in the modulation of breast cancer progression are exosome-mediated. p-Rasal2 expression in ER+ breast cancer cells and exosomes, cancer tissues and blood was significantly lower than in ER− tumour cells and patients. INTERPRETATION: p-Rasal2 facilitates tumour progression in both ER+ and ER− breast cancers. The ratio of p-Rasal2/non-p-Rasal2 in ER+ and ER− breast cancers is one of the factors deciding the role of Rasal2 (or total Rasal2) as a suppressor in ER+ breast cancers or as a promoter in ER− breast cancers. Targeting the phosphorylation of Rasal2 machinery may therefore be useful as a therapy to restrain breast cancer progression by reducing p-Rasal2/non-p-Rasal2 ratio, especially in ER− breast cancers. FUND: NSFC and Hong Kong Research Grants Council.