An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells

Abstract

BackgroundAcquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance.ResultsThrough genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR.ConclusionThese findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.

Tumor MicroRNA Expression Profiling Identifies Circulating MicroRNAs for Early Breast Cancer Detection

“…MiR125b-5p has also been reported to be upregulated in the serum of breast cancer patients (28,32 ) and has been associated with chemotherapeutic resistance, nonresponsive patients having higher expression levels. Finally, upregulation of miR-96-5p and downregulation of miR-505-5p have been reported in breast tumors and related to increased cell proliferation (33,34 ), but this is the first time that their circulating levels are associated with breast cancer, both being overexpressed.…”

miRNA Dysregulation in Breast Cancer

“…More recently, these miRNAs were shown to induce resistance to the pure antiestrogen, fulvestrant, In vitro (67) attributed in part to the activation of b-catenin and the repression of TGF-b-mediated growth inhibition (74). In the first in vivo study of miR-222, it was found that it was possible to suppress the growth of tamoxifen-resistant xenografts through the administration of an anti-miR directly to the tumor (75).…”

Usefulness of miRNA profiles for predicting pathological responses to neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer

“…Twenty-one miRNAs were differentially expressed between the non-pCR and pCR groups in the analysis of all 40 patients with HER2-positive breast cancer (Table III). Nine of these 21 miRNAs are reported to be associated with breast cancer (17)(18)(19)(20)(21)(22)(23)(24)(25). The other 12 miRNAs have no reported correlation with breast cancer.…”

“…For the luminal B-like (HER2-positive) subtype, 17 miRNAs were differentially expressed (Table IV), and nine of these 17 miRNAs are reported to be correlated with breast cancer (20)(21)(22)24,(26)(27)(28)(29)(30). For the HER2-positive (non luminal) subtype, 14 miRNAs were differentially expressed (Table V), and five of these are reported to be correlated with breast cancer (17,23,25,31,32). The miRNA expression profiles associated with pathological response differed completely between the HER2-positive (non luminal) and luminal B-like (HER2-positive) subtypes.…”

“…miR-218 was downregulated in cisplatin-resistant breast cancer cell lines and regulated chemosensitivity by targeting BRCA1 (23). miR-505 has been reported as a tumor-suppressive miRNA, and is inversely correlated with Akt3, which modulates drug sensitivity (25). The remaining differentially expressed 15 miRNAs between the non-pCR and pCR groups are reportedly involved in the progression of breast cancer (Tables III-V).…”