| dc.description.abstract | Breast cancer cells frequently home to the bone marrow, where they encounter signals that promote survival and quiescence or stimulate their proliferation. However, our mechanistic understanding of bone dissemination and metastatic outgrowth remains poorly understood. The interleukin-6 (IL-6) cytokines signal through the co-receptor glycoprotein130 (gp130) and are abundantly secreted within the bone microenvironment and have been implicated as factors that modulate tumor dormancy and metastasis. The gp130 cytokine family regulates a plethora of biological processes that affect bone remodeling, cancer progression, and metastasis, and questions remain as to the exact role these cytokines play in tumor dormancy. To address some of the current gaps within the field pertaining to the role of the gp130 cytokines in breast cancer, we first sought to characterize the gp130 cytokines in breast cancer. We found that expression of the cytokine receptors is considerably lower in estrogen receptor negative (ER-) compared to estrogen receptor positive (ER+) disease, and patients with downregulation of the cytokines or receptors were associated with reduced relapse-free survival. Functionally, overexpression of oncostatin M (OSM) increased ER+ breast cancer bone dissemination and reverse-phase protein array revealed distinct and overlapping pathways stimulated by OSM, leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) with known roles in breast cancer progression and metastasis. Taken together, these data establish the role for OSM in ER+ breast cancer dissemination to bone and reveal distinct signaling pathways stimulated by the gp130 cytokines in breast cancer cells. To determine a mechanism for OSM—mediated bone dissemination in ER+ breast cancer, we evaluated whether OSM expression expands the cancer stem cell (CSC) population in vitro in ER+ breast cancer cells. Paracrine OSM led to an increase in CD44 expression (a cell surface marker important for the characterization of CSCs) in ER+ breast cancer cells. Autocrine and paracrine OSM did not significantly change the CSC population (CD44High/CD24Low) at the time points examined, but further studies are necessary to elucidate whether OSM regulates CD44 and the CSC population to promote bone colonization in ER+ breast cancer. | |
