Hsa-miR-375/RASD1 Signaling May Predict Local Control in Early Breast Cancer

Abstract

Background: In order to characterize the various subtypes of breast cancer more precisely and improve patients selection for breast conserving therapy (BCT), molecular profiling has gained importance over the past two decades. MicroRNAs, which are small non-coding RNAs, can potentially regulate numerous downstream target molecules and thereby interfere in carcinogenesis and treatment response via multiple pathways. The aim of the current two-phase study was to investigate whether hsa-miR-375-signaling through RASD1 could predict local control (LC) in early breast cancer. Results: The patient and treatment characteristics of 81 individuals were similarly distributed between relapse (n = 27) and control groups (n = 54). In the pilot phase, the primary tumors of 28 patients were analyzed with microarray technology. Of the more than 70,000 genes on the chip, 104 potential hsa-miR-375 target molecules were found to have a lower expression level in relapse patients compared to controls (p-value < 0.2). For RASD1, a hsa-miR-375 binding site was predicted by an in silico search in five mRNA-miRNA databases and mechanistically proven in previous pre-clinical studies. Its expression levels were markedly lower in relapse patients than in controls (p-value of 0.058). In a second phase, this finding could be validated in an independent set of 53 patients using ddPCR. Patients with enhanced levels of hsa-miR-375 compared to RASD1 had a higher probability of local relapse than those with the inverse expression pattern of the two markers (log-rank test, p-value = 0.069). Conclusion: This two-phase study demonstrates that hsa-miR-375/RASD1 signaling is able to predict local control in early breast cancer patients, which—to our knowledge—is the first clinical report on a miR combined with one of its downstream target proteins predicting LC in breast cancer.

Computational Identification of Sex-Biased Biomarker MicroRNAs and Genes Associated with Immune Infiltration in Breast Cancer

“…We acquired 29 X-linked miRNAs from published studies, as mentioned in the Materials and Methods section. Ten of these X-linked miRNAs were related to breast cancer [ 18 , 22 , 23 , 25 , 26 ] ( Supplementary Table S5 ). Under the assumption that miRNAs differentially expressed in females of different ages are highly likely female-biased, we searched such a miRNA list against 96 differentially expressed miRNAs associated with breast cancer reported in the study [ 28 ].…”

“…To make sure that we have included all possible X-linked miRNAs associated with breast cancer, we investigated existing literatures focusing on studies about X-linked miRNAs [ 7 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Using a customized R program, we identified female-biased breast cancer genes and their X-linked targeting miRNAs to search against the inversely correlated mRNA-miRNA pairs from Dai et al (2018) [ 12 ].…”

MicroRNA-375: potential cancer suppressor and therapeutic drug

“…The up-regulated expression of hsa-miR-375 accelerates cell proliferation by regulating the PI3K/Akt/mTOR pathway, and the overexpression of Ras-related dexamethasone-induced 1 (RASD1) reduces the activity of the Akt/mTOR pathway [ 41 ]. Zellinger et al analyzed 53 BC patients and found that patients with low miR-375 expression were more likely to have a local recurrence, which was probably related to RASD1 signaling [ 42 ]. Additionally, miR-375 was also found to be involved in the growth of fulvestrant-resistant breast cancer (FRBC) cells and reducing autophagy [ 43 ].…”

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

“…The miRNA miR-375, which can regulate CELF6, is thought to be associated with pancreatic cancer and breast cancer [138][139][140][141]. In breast cancer, higher levels of miR-375 were expressed in ER-α-positive, where it was a critical factor in cell proliferation and an early event in tumorigenesis [142].…”

“…A single nucleotide variation, rs4777498, in CELF6, regulated by miR-375, was previously found to be associated with cervical cancer susceptibility [117]. The upregulation of miR-375 is a key driver of cell proliferation and patients with miR-375 overexpression have a higher probability of local relapse in early breast cancer [140].…”