gp130 Cytokines Activate Novel Signaling Pathways and Alter Bone Dissemination in ER+ Breast Cancer Cells.

Breast cancer cells frequently home to the bone marrow, where they encounter signals that promote survival and quiescence or stimulate their proliferation. The interleukin-6 (IL-6) cytokines signal through the co-receptor glycoprotein130 (gp130) and are abundantly secreted within the bone microenvironment. Breast cancer cell expression of leukemia inhibitory factor (LIF) receptor (LIFR)/STAT3 signaling promotes tumor dormancy in the bone, but it is unclear which, if any of the cytokines that signal through LIFR, including LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), promote tumor dormancy and which signaling pathways are induced. We first confirmed that LIF, OSM, and CNTF and their receptor components were expressed across a panel of breast cancer cell lines, although expression was lower in estrogen receptor-negative (ER- ) bone metastatic clones compared with parental cell lines. In estrogen receptor-positive (ER+ ) cells, OSM robustly stimulated phosphorylation of known gp130 signaling targets STAT3, ERK, and AKT, while CNTF activated STAT3 signaling. In ER- breast cancer cells, OSM alone stimulated AKT and ERK signaling. Overexpression of OSM, but not CNTF, reduced dormancy gene expression and increased ER+ breast cancer bone dissemination. Reverse-phase protein array revealed distinct and overlapping pathways stimulated by OSM, LIF, and CNTF with known roles in breast cancer progression and metastasis. In breast cancer patients, downregulation of the cytokines or receptors was associated with reduced relapse-free survival, but OSM was significantly elevated in patients with invasive disease and distant metastasis. Together these data indicate that the gp130 cytokines induce multiple signaling cascades in breast cancer cells, with a potential pro-tumorigenic role for OSM and pro-dormancy role for CNTF.