Identification and Validation of Oncologic miRNA Biomarkers for Luminal A-like Breast Cancer

Abstract

IntroductionBreast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting.MethodsBlood samples were prospectively collected from patients with Luminal A-like breast cancer (n = 54) and controls (n = 56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n = 10 Luminal A-like; n = 10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n = 44 Luminal A; n = 46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated.ResultsMicroarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis (miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652). The biomarker potential of 4 miRNAs (miR-29a, miR-181a, miR-223 and miR-652) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p = 0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs (miR-29a, miR-181a and miR-652) could reliably differentiate between cancers and controls with an AUC of 0.80.ConclusionThis study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype-specific breast tumor detection.

miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer

“…Therefore, miR-93, rather than the whole cluster and its host gene, may play a critical role in the acquisition of drug resistance in breast cancer. To date, very few studies have focused on the role of miR-93 in breast cancer (30)(31)(32)(33)(34)(35)(36). Furthermore, these studies only reported its association with altered expression patterns and proliferation, and none have focused on its relationship with drug resistance and association with PTEN.…”

Application of omic technologies in cancer research

“…78 This method was successfully applied for the discovery of altered miRNAs between luminal A breast cancer patients and healthy controls. 79 …”

Association of microRNA-93, 190, 200b and Receptor Status in Core Biopsies from Stage III Breast Cancer Patients

“…These particular miRNAs were selected on the basis of previous reports in the literature, the miRNA database, and communications from breast cancer conferences. They represent a broad range of epigenetic pathways involved in migration, invasion, receptor status, epithelialto-mesenchymal transition, cancer dormancy, switch to the fast growing phenotype, drug resistance, etc (Blenkiron et al, 2007;Lowery et al, 2008;Fang et al, 2012;Liu et al, 2012;Manavalan et al, 2013;Lehmann, 2014;Li et al, 2014;McDermott et al, 2014;www.mirbase.org). We also used unpublished data of TaqMan Low Density Arrays from our previous research.…”

“…Breast cancerrelated genes have been extensively investigated (Ellis and Perou, 2013), but much less is known about epigenetic alterations such as microRNAs (miRNAs), DNA methylation, or histone modifications (Lehmann, 2014;Li et al, 2014;McDermott et al, 2014). MiRNAs are single-stranded, small noncoding RNAs, *18-25 nucleotides in length that potentially may modify up to one-third of the human genome (Fang et al, 2012;Li et al, 2014;McDermott et al, 2014). They were first identified over a decade ago and in February 2014, a total of 2578 human miRNAs were registered in mirbase.org (www.mirbase.org).…”

“…They were first identified over a decade ago and in February 2014, a total of 2578 human miRNAs were registered in mirbase.org (www.mirbase.org). It has recently been recognized that deregulation of certain miRNAs is associated with carcinogenesis by means of oncogenes, while others act as tumor suppressors (Fang et al, 2012;Li et al, 2014;McDermott et al, 2014). It has also been speculated that certain miRNAs perform different functions in early and advanced stages of cancer (Li et al, 2014).…”