TY - JOUR
T1 - Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells
AU - Ambrosio, Maria Rosaria
AU - D'Esposito, Vittoria
AU - Costa, Valerio
AU - Liguoro, Domenico
AU - Collina, Francesca
AU - Cantile, Monica
AU - Prevete, Nella
AU - Passaro, Carmela
AU - Mosca, Giusy
AU - De Laurentiis, Michelino
AU - Di Bonito, Maurizio
AU - Botti, Gerardo
AU - Franco, Renato
AU - Beguinot, Francesco
AU - Ciccodicola, Alfredo
AU - Formisano, Pietro
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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. Coculturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocytereleased 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.
AB - 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. Coculturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocytereleased 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.
KW - Adipose tissue
KW - Breast cancer
KW - Connective tissue growth factor
KW - Glucose
KW - Tamoxifen
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U2 - 10.18632/oncotarget.22552
DO - 10.18632/oncotarget.22552
M3 - Article
AN - SCOPUS:85037702603
VL - 8
SP - 109000
EP - 109017
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 65
ER -