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

// Maria Rosaria Ambrosio 1, * , Vittoria D’Esposito 1, * , Valerio Costa 2 , Domenico Liguoro 1 , Francesca Collina 3 , Monica Cantile 3 , Nella Prevete 1 , Carmela Passaro 1 , Giusy Mosca 1 , Michelino De Laurentiis 4 , Maurizio Di Bonito 3 , Gerardo Botti 3 , Renato Franco 5 , Francesco Beguinot 1 , Alfredo Ciccodicola 2, 6 and Pietro Formisano 1 1 Department of Translational Medicine, University of Naples “Federico II” & URT “Genomic of Diabetes” of Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Council of Research (CNR), Naples 80131, Italy 2 Institute of Genetic and Biophysics “A. Buzzati-Traverso”, CNR, Naples 80131, Italy 3 Pathology Unit, National Cancer Institute “G. Pascale Foundation”, Naples 80131, Italy 4 Department of Breast Surgery and Cancer Prevention, National Cancer Institute “G. Pascale Foundation”, Naples 80131, Italy 5 Pathology Unit, Universita degli Studi della Campania “Luigi Vanvitelli”, Naples 80138, Italy 6 Department of Science and Technology, University of Naples “Parthenope”, Naples 80131, Italy * These authors have equally contributed to this work Correspondence to: Pietro Formisano, email: fpietro@unina.it Keywords: breast cancer; tamoxifen; glucose; adipose tissue; connective tissue growth factor Received: April 21, 2017 Accepted: July 25, 2017 Published: November 20, 2017 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.