Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin-estrogen receptor loop signaling.
Cancer Lett
; 523: 82-99, 2021 12 28.
Article
em En
| MEDLINE
| ID: mdl-34610415
ABSTRACT
Many breast cancer patients harbor high estrogen receptor (ER) expression in tumors that can be treated with endocrine therapy, which includes aromatase inhibitors (AI); unfortunately, resistance often occurs. Mitochondrial dysfunction has been thought to contribute to progression and to be related to hormone receptor expression in breast tumors. Mitochondrial alterations in AI-resistant breast cancer have not yet been defined. In this study, we characterized mitochondrial alterations and their roles in AI resistance. MCF-7aro AI-resistant breast cancer cells were shown to have significant changes in mitochondria. Low expressions of mitochondrial genes and proteins could be poor prognostic factors for breast cancer patients. Long-term mitochondrial inhibitor treatments-mediated mitochondrial stress adaptation could induce letrozole resistance. ERα-amphiregulin (AREG) loop signaling was activated and contributed to mitochondrial stress adaptation-mediated letrozole resistance. The up-regulation of AREG-epidermal growth factor receptor (EGFR) crosstalk activated the PI3K/Akt/mTOR and ERK pathways and was responsible for ERα activation. Moreover, mitochondrial stress adaptation-increased intracellular levels of reactive oxygen species (ROS) and calcium were shown to induce AREG expression and secretion. In conclusion, our results support the claim that mitochondrial stress adaptation contributes to AI resistance via ROS/calcium-mediated AREG-ERα loop signaling and provide possible treatment targets for overcoming AI resistance.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Receptores de Estrogênio
/
Cálcio
/
Espécies Reativas de Oxigênio
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Inibidores da Aromatase
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Anfirregulina
/
Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2021
Tipo de documento:
Article