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The synergy between miR-486–5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells
- Source :
- Biomedicine & Pharmacotherapy, Vol 141, Iss, Pp 111925-(2021), Mansoori, B, Najafi, S, Mohammadi, A, AsadollahSeraj, H, Savadi, P, Mansoori, B, Nazari, A, Mokhtarzadeh, A, Roshani, E, Duijf, P HG, Cho, W C S & Baradaran, B 2021, ' The synergy between miR-486–5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells ', Biomedicine and Pharmacotherapy, vol. 141, 111925 . https://doi.org/10.1016/j.biopha.2021.111925
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486–5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486–5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486–5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486–5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486–5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486–5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC. Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486–5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486–5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486–5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486–5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486–5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486–5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC.
- Subjects :
- HMGA1
Programmed cell death
Antineoplastic Agents, Hormonal
MiR-486–5p
drug-resistant
Cell
Population
Estrogen receptor
Breast Neoplasms
RM1-950
Breast cancer
breast cancer
Humans
Medicine
skin and connective tissue diseases
education
Drug-resistant
Pharmacology
education.field_of_study
Cell Death
Dose-Response Relationship, Drug
tamoxifen
business.industry
Cancer
Cell migration
General Medicine
medicine.disease
MicroRNAs
Tamoxifen
HEK293 Cells
medicine.anatomical_structure
Drug Resistance, Neoplasm
MCF-7 Cells
Cancer research
Female
Therapeutics. Pharmacology
business
medicine.drug
Subjects
Details
- ISSN :
- 07533322
- Volume :
- 141
- Database :
- OpenAIRE
- Journal :
- Biomedicine & Pharmacotherapy
- Accession number :
- edsair.doi.dedup.....9101f21f733afbaf3b09edb5c78cc7dd