Endocrine resistance and tumor microenvironment: spatial association between ER and 1 integrin

ROCIO SAMPALLO; TOSCANI ANDRES MARTIN; COLUCCIO LESKOW FEDERICO; SIMIAN, MARINA

Bariloche

Congreso; Sistam 2012; 2012

Endocrine resistance and tumor microenvironment: spatial association between ER and 1 integrin Sampayo, R1, Toscani, AM2, Coluccio-Leskow, F2 & Simian, M1. 1-Research Area, Institute of Oncology "Ángel H. Roffo", UBA, Buenos Aires, Argentina. 2-Department of Biological Chemistry, IQUIBICEN-CONICET, School of Exact and Natural Sciences, UBA, Buenos Aires, Argentina. Every day, four thousand women are diagnosed with breast cancer. For most of them, the therapy of choice is tamoxifen (TAM) endocrine therapy. TAM is a selective estrogen receptor (ER) modulator acting as an antagonist in the breast and interfering with the development of ER-positive breast tumors. However, 35% of these patients do not respond accurately to the therapy and cancer reappears. Therefore, understanding the mechanisms involved in development of TAM resistance is critical to increase the efficiency of therapy and, consequently, prolong the life of millions of women worldwide. In this sense, we have previously described, in the human MCF7 cell line, that extracellular matrix (ECM) components of the tumor micro-environment determine their sensitivity to TAM. In particular, fibronectin (FN), one of the most abundant components of the ECM, confers TAM resistance to these cells and leads to ER-phosphorylation at serine 118. In the present work we have deepened our understanding of the molecular events that are involved in FN mediated TAM resistance. Using two human mammary cell lines, MCF7 and T47D, we find that the main receptor for FN, 1 integrin, coimmunoprecipitates and colocalizes with ERat the cell membrane. Additionally, we observed that ER and 1 integrin interact at the cell membrane in point-like focal adhesion complexes. Together with this, we show how estrogens are capable of strongly restraining the adhesion of these cells to FN. We believe our findings could lead to new therapeutic alternatives to be used in combination with endocrine therapies, in which the architecture of the ECM would be the key molecular target to be considered.