Abstract
Breast cancer is the most common women’s malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles in regulating key cellular processes by suppressing gene expression. However, additive opportunities involving miRNAs have been underexplored. For example, both miR-34a and miR-200c individually suppress the development of different types of cancer, but the cellular effects of their combined actions remain unknown. Here, we show that miR-34a and miR-200c levels are reduced in breast tumors compared to adjacent normal tissues and that this additively predicts poor patient survival. In addition, in cell lines, miR-34a and miR-200c additively induce apoptosis and cell cycle arrest, while also inhibiting proliferation, invasion, migration, stemness and epithelial-to-mesenchymal transition (EMT). Mechanistically, both miRNA-34a and miR-200c directly target HIF1-α and subsequently downregulate VEGFR, MMP9 and CXCR4, although combined miRNA-34a and miR-200c delivery suppresses mouse xenograft tumor development as effectively as individual delivery. We establish a model, supported by in vitro and clinical data, which collectively suggest that the co-delivery of miR-34a and miR-200c represents a promising novel therapeutic strategy for breast cancer patients.
Highlights
Human breast cancer (BC) is known as the most common malignancy among women.It is caused by somatic genetic and genomic alterations in breast cells [1,2]
We found that reduced miR-34a and miR-200c expression are significantly associated with poor BC patient survival in more malignant types of BC, which are negative for estrogen receptor expression (p < 0.05, as per both log-rank and Cox proportional hazard tests for each miRNA) (Figure 1D,E)
The expression level of both miR-34a and miR-200c in normal breast cell line was significantly higher than invasive and noninvasive BC cell lines (p < 0.0001) (Figure 1G). These results indicate that miR-34a and miR-200c are downregulated in breast cancer and invasive breast cancer cell lines, and that they are associated with poor patient survival
Summary
Human breast cancer (BC) is known as the most common malignancy among women. It is caused by somatic genetic and genomic alterations in breast cells [1,2]. Recent advances in surgical, chemo, radio- and hormone-therapy for BC have improved the outcomes, there are still subgroups of BC patients with high morbidity and the underlying causes are not always clear. Some events, such as recurrence, metastasis, and resistance to chemo- and radiotherapy, provide a poor prognosis. The lack of diagnostic and therapeutic markers for targeted therapy approaches is a major barrier to improving treatment for some patient groups
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