Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells.

Gerardo Botti,Carmela Passaro,Domenico Liguoro,Monica Cantile,Francesco Beguinot,Maria Rosaria Ambrosio,Vittoria D’Esposito,Valerio Costa,Nella Prevete,Renato Franco,Giusy Mosca,Alfredo Ciccodicola,Francesca Collina,Michelino De Laurentiis,Maurizio Di Bonito,Pietro Formisano

doi:10.18632/oncotarget.22552

Abstract

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.

Highlights

Breast cancer (BC) is the most common female malignant neoplasia with the highest incidence in the industrialized world [1]
Of note, shifting HG cells to LG (HG→LG), ameliorated tamoxifen responsiveness determining a significant reduction of cell viability (≈40%; p
We demonstrated that breast cancer (BC) cells cultured in a glucose concentration resembling hyperglycemia (HG) in humans are less sensitive to tamoxifen than cells grown in a concentration corresponding to normal fasting glucose levels (LG)

Summary

Introduction

Breast cancer (BC) is the most common female malignant neoplasia with the highest incidence in the industrialized world [1]. Type 2 diabetes (T2D) is associated with a 20% increased risk of BC and a more aggressive phenotype [2, 3]. Hyperglycemia is correlated with a poorer therapeutic outcome and reduced drug response in BC [5, 6, 7]. Enhanced glucose uptake is a well-known metabolic hallmark of cancer cells [8]. The anabolic urge of tumor cells drives them to adapt with profound metabolic changes, among which the most remarkable is known as the ‘Warburg effect’ [9]. Hyperglycemia may be responsible for the excess of glucose supply for glucosewww.impactjournals.com/oncotarget hungry cancer cells, contributing to a more aggressive phenotype [10]. A possible effect of diabetes-related hyperglycemia on the outcome of chemotherapy for BC should not be neglected

Methods

Results

Conclusion