The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8

Autor: Chen-liang Guo, Jia-jie Shi, Si-meng Chen, Yi Xue Li, Linghua Meng, Jian Ding
Rok vydání: 2017
Předmět:
0301 basic medicine
Cell cycle checkpoint
Morpholines
Population
Cell
Estrogen receptor
Down-Regulation
Antineoplastic Agents
Breast Neoplasms
Protein Serine-Threonine Kinases
Article
03 medical and health sciences
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Cell Line
Tumor
Medicine
Humans
Pharmacology (medical)
education
skin and connective tissue diseases
Protein Kinase Inhibitors
Heat-Shock Proteins
Pharmacology
education.field_of_study
business.industry
TOR Serine-Threonine Kinases
Estrogen Receptor alpha
General Medicine
medicine.disease
Prognosis
G1 Phase Cell Cycle Checkpoints
Tamoxifen
030104 developmental biology
medicine.anatomical_structure
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
business
Estrogen receptor alpha
medicine.drug
Molecular Chaperones
Zdroj: Acta pharmacologica Sinica. 39(8)
ISSN: 1745-7254
Popis: Tamoxifen, an important endocrine therapeutic agent, is widely used for the treatment of estrogen receptor positive (ER(+)) breast cancer. However, de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments. In this study, we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance. HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells. Moreover, high expression of HSPB8 associates with poor prognosis in ER(+) breast cancer patients but not in patients without classification. Stimulating ER signaling by heterogeneous expression of ERa or 17β-estradiol promotes HSPB8 expression and reduces the cell population in G(1) phase. In contrast, blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8. In addition, knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G(1) phase. AZD8055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells, which was associated with down-regulation of HSPB8. We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER(+) breast cancer cells. Thus, AZD8055 was able to overcome tamoxifen resistance in breast cancer cells, and the expression of HSPB8 may predict the efficacy of AZD8055 in ER(+) breast cancer. This hypothesis deserves further investigation.
Databáze: OpenAIRE
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