期刊
ONCOTARGET
卷 8, 期 65, 页码 109000-109017出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22552
关键词
breast cancer; tamoxifen; glucose; adipose tissue; connective tissue growth factor
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG19001]
- European Foundation for the Study of Diabetes (EFSD/Diabetes and Cancer Programme) [2016/0052351]
- European Foundation for the Study of Diabetes (EFSD/Lilly Research Fellowship Programme) [2016/0052351]
- European Foundation for the Study of Diabetes [Lilly FS 2016_8] Funding Source: researchfish
Type 2 diabetes and obesity are negative prognostic factors in patients with breast cancer (BC). We found that sensitivity to tamoxifen was reduced by 2-fold by 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in MCF7 BC cells. Shifting from HG to LG ameliorated MCF7 cell responsiveness to tamoxifen. RNA-Sequencing of MCF7 BC cells revealed that cell cycle-related genes were mainly affected by glucose. Connective Tissue Growth Factor (CTGF) was identified as a glucose-induced modulator of cell sensitivity to tamoxifen. Co-culturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocyte-released IL8 reverted these effects. Interestingly, CTGF immuno-detection in bioptic specimens from women with estrogen receptor positive (ER+) BC correlated with hormone therapy resistance, distant metastases, reduced overall and disease-free survival. Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting IL8 release by adipocytes.
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