Impact of diabetes on promoting the growth of breast cancer.
Cancer Commun (Lond)
; 41(5): 414-431, 2021 05.
Article
en En
| MEDLINE
| ID: mdl-33609419
ABSTRACT
BACKGROUND:
Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.METHODS:
We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.RESULTS:
Treatment with metformin/rosiglitazone in MMTV-ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13 C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.CONCLUSIONS:
MMTV-ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Diabetes Mellitus Tipo 2
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Cancer Commun (Lond)
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos