Abstract LB-314: Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1

Abstract

Abstract Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin (α-SMA) and fibroblast activating protein. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through crosstalk with them. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. We found the increased expression of α-SMA in human breast tumor tissues compared with normal adjacent tissues. In particular, α-SMA was highly expressed in the most of estrogen receptor (ER)-negative tumor tissues. When ER-negative breast cancer MDA-MB-231 cells and MDA-MB-468 cells were treated with the CAF-conditioned medium (CM), the cell viability was significantly elevated. In addition, MDA-MB-231 cells exhibited elevated expression of proliferative and invasive genes when incubated with CAFs. Notably, fibroblast growth factor-2 (FGF2) expression was correlated with the presence of CAFs. We noticed that mRNA level of FGF2 in CAFs as well as the concentration of FGF2 in CAF-CM was higher than that in normal fibroblasts. FGF2 exerts its biological effects by binding to FGF receptor 1 (FGFR1). In the breast cancer tissue microarray, 42% ER-negative patients co-expressed FGF2 and FGFR1 proteins, whereas only 19% ER-positive patients co-expressed those proteins. While the expression of FGFR1 was up-regulated in breast cancer cells, another major FGF2-corresponding receptor FGFR2 was barely expressed.This prompted us to explore FGF2-FGFR1 signaling in the context of paracrine communication. CAF-stimulated MDA-MB-231 cell migration and invasion as well as FGFR1 signaling activation were abolished when FGF2-neutralizing antibody was added to the CAF-CM. In a xenograft mouse model, co-injection of shmock-MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, which suggests that stromal-derived FGF2 enhances tumor formation through activation of FGFR1 in cancer cells. Furthermore, FGF2 promotes nuclear localization of FGFR1 which might be associated with cancer cell proliferation and migration. In conclusion, secretion of FGF2 by CAFs stimulates proliferation and migration of breast cancer cells through interaction with FGFR1 which may contribute to human breast cancer progression. Citation Format: Jinyoung Suh, Do-Hee Kim, Hye-Kyung Na, Young-Joon Surh. Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-314.