The synergy between miR-486-5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells.
Biomed Pharmacother
; 141: 111925, 2021 Sep.
Article
en En
| MEDLINE
| ID: mdl-34323695
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tamoxifeno
/
Neoplasias de la Mama
/
Muerte Celular
/
Resistencia a Antineoplásicos
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Antineoplásicos Hormonales
/
MicroARNs
Tipo de estudio:
Etiology_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Biomed Pharmacother
Año:
2021
Tipo del documento:
Article
País de afiliación:
Dinamarca