Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2
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Jar-Yi Ho1,*, Ren-Jun Hsu1,2,*, Chih-Hsi Wu1, Guo-Shiou Liao3, Hong-Wei Gao1, Tong-Hong Wang4, Cheng-Ping Yu1,2
1Department of Pathology, and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
4Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
*These authors have contributed equally to this work
Cheng-Ping Yu, email: email@example.com
Keywords: miR-550a-3p, ERK1, ERK2, Ras/ERK signaling, breast cancer
Received: March 29, 2016 Accepted: July 10, 2016 Published: July 23, 2016
Hyperactivation of the Ras/ERK pathway contributes to breast cancer initiation and progression, and recent evidence suggests aberrant signaling of miRNAs that regulate the Ras/ERK pathway play important roles during carcinogenesis and cancer progression. In this study, we demonstrate that miR-550a-3p expression is negatively correlated with levels of ERK1 and ERK2, two pivotal effectors in the Ras/ERK pathway. MiR-550a-3p gradually decreased during breast cancer initiation and progression and this reduction was a prognostic indicator of poorer overall survival (OS) and disease-free survival (DFS) among breast cancer patients. Our mechanistic studies demonstrated that miR-550a-3p exerts its tumor-suppressor role by directly repressing ERK1 and ERK2 protein expression, thereby suppressing the oncogenic ERK/RSK cascades, which reduced breast cancer cell viability, survival, migration, invasion, tumorigenesis, and metastasis. The inhibitory effects of miR-550a-3p were rescued by ectopic expression of ERK1 and/or ERK2. The novel connection between miR-550a-3p and ERK defines a new diagnostic and prognostic role for miR-550a-3p and highlights ERK inhibition as a candidate therapeutic target for breast cancers exhibiting hyperactivated Ras/ERK signaling.
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