Abstract
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.
Highlights
Breast cancer is the most common female cancer and ranks among the leading causes of morbidity and mortality worldwide [1]; among Taiwanese women it occupies the top spot for morbidity and is fourth in mortality [2]
MiR-550a-3p was significantly more highly expressed in the nontumorigenic human breast epithelial cell line H184B5F5/M10 than in breast cancer cell lines, and less miR-550a-3p was observed in poorly differentiated breast cancer cell lines (Figure 1A)
We found the expression of the microRNA miR-550a-3p was negatively correlated with protein levels of ERK1 and ERK2, two pivotal effectors in the oncogenic Ras/ERK pathway, and ascribed significant diagnostic and prognostic values to the downregulation of miR-550a-3p during breast cancer initiation and progression
Summary
Breast cancer is the most common female cancer and ranks among the leading causes of morbidity and mortality worldwide [1]; among Taiwanese women it occupies the top spot for morbidity and is fourth in mortality [2]. The RAS/extracellular signal regulated kinase (ERK) pathway is reported to enhance initiation and progression of several types of breast cancer and to promote cancer aggressiveness in a number of experimental models [3]. Ras/ERK hyperactivation is a common feature of a variety of tumor types featuring activating KRAS, NRAS, or BRAF gene mutations [7]; mutations in the pathway are detected in only ∼3.2% of all breast lesions [8]. The Ras/ERK pathway is frequently activated as a consequence of alterations in upstream regulators or downstream effectors [5, 6]. Hyperactivation of the Ras/ ERK pathway has been observed in approximately 50% of breast cancers [9, 10] and is significantly associated with advanced breast cancer progression and poorer prognosis [11,12,13]. ERK1 and ERK2 are overexpressed in 26%–45% of all molecular subtypes of breast cancer [21], which implies that the Ras/ERK pathway is more frequently activated by other mechanisms in breast cancer such as genomic or epigenetic variation of other pathway components [9, 11, 17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
