MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast

T Ujihira1, K Ikeda2, T Suzuki3

  • 11] Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan [2] Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan.

Scientific Reports
|January 7, 2015
PubMed

Insights

This study identified microRNAs (miRNAs) involved in tamoxifen response in breast cancer. Downregulation of miR-574-3p was linked to tamoxifen resistance, suggesting it as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Estrogen receptor α (ERα) is a key target in breast cancer therapy.
  • Tamoxifen resistance is a significant clinical challenge in ERα-positive breast cancer.
  • MicroRNAs (miRNAs) play crucial roles in gene regulation and cancer progression.

Purpose of the Study:

  • To identify microRNAs (miRNAs) associated with tamoxifen response in breast cancer.
  • To investigate the role of specific miRNAs in acquired endocrine resistance.
  • To explore potential miRNA-based therapeutic strategies for tamoxifen-resistant breast cancer.

Main Methods:

  • Functional screening of a lentiviral miRNA library in MCF-7 breast cancer cells treated with 4-hydroxytamoxifen (OHT).
  • Microarray analysis to quantify miRNA precursor integration and identify differentially expressed miRNAs.
  • In silico analysis and luciferase reporter assays to validate miRNA-target interactions.

Main Results:

  • Five 'dropout' miRNAs (downregulated) and six 'retained' miRNAs (upregulated) were identified in response to OHT treatment.
  • miR-574-3p was found to be downregulated in clinical breast cancer tissues and its inhibition reversed tamoxifen-mediated growth suppression.
  • Clathrin heavy chain (CLTC) was validated as a direct target of miR-574-3p, with inverse expression patterns.

Conclusions:

  • Functional miRNA screening is effective for discovering genes involved in tamoxifen response.
  • miR-574-3p downregulation contributes to tamoxifen resistance in breast cancer by upregulating CLTC.
  • Targeting miR-574-3p or its downstream effectors may offer novel therapeutic avenues for endocrine-resistant breast cancer.

Related Concept Videos

MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
4.4K
MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
25.1K
MicroRNAs01:22

MicroRNAs

12.1K
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
6.5K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K