Over-expression of miR-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3ζ, estrogen receptor α, and autophagy.

Abstract

AIM:

To investigate the effects and mechanisms of miR-451a in the tamoxifen (TAM) resistance of breast cancer cells.

MATERIALS AND METHODS:

TAM sensitive cells (MCF-7) and resistant cells (LCC2) were employed in the study. The lentivirus vectors of Lv-miR-451a, Lv-miR-451a sponge, and Lv-miR-451a NC were employed to increase or decrease the expression of miR-451a, respectively. SiRNA to 14-3-3ζ was used to inhibit expression of 14-3-3ζ. MTT assay was utilized to detect breast cancer cell proliferation. AnnexinV-FITC binding assay was used to detect apoptosis. Expression of ERα, 14-3-3ζ and miR-451a were measured by qRT-PCR and Western blot analysis. Interactions between 14-3-3ζ and ERα were investigated by co-immunoprecipitation. LC3-II surface expression and intracellular autophagosomes were observed by Western blot and electron microscopy.

KEY FINDINGS:

Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3ζ expression, and down-regulate ERα expression. 14-3-3ζ and ERα were shown to interact. Over-expression of miR-451a decreased 14-3-3ζ expression and increased ERα expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AKT and p-mTOR. R18 can significantly decrease cell proliferation and increase apoptosis. R18 and 14-3-3ζ siRNA can rescue the effects of down-regulation of ERα by knocking down miR-451a. Over-expression of miR-451a inhibits autophagy, knocking-down miR-451a stimulates autophagy.

SIGNIFICANCE:

MiR-451a functions as a suppressor of resistance to TAM through regulating autophagy, the expression of 14-3-3ζ and ERα. This suggests miR-451a to be a potential target for reversing resistance to TAM.

• Authors: Zhen-Ru Liu, Yi Song, Li-Hong Wan, Yuan-Yuan Zhang, Li-Mimg Zhou
• Journal: Life sciences (Life Sci) Vol. 149 Pg. 104-13 (Mar 15 2016) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26896688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 14-3-3 Proteins
• Antineoplastic Agents, Hormonal
• ESR1 protein, human
• Estrogen Receptor alpha
• MIRN451 microRNA, human
• MicroRNAs
• Tamoxifen

Topics

• 14-3-3 Proteins (antagonists & inhibitors, biosynthesis)
• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Autophagy (drug effects, physiology)
• Breast Neoplasms (drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Estrogen Receptor alpha (antagonists & inhibitors, biosynthesis)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• MicroRNAs (biosynthesis)
• Tamoxifen (pharmacology, therapeutic use)