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

Abstract

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. © 2021 American Society for Bone and Mineral Research (ASBMR).

The IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer

“…Several studies have reported growth-inhibitory effects of OSM in BC cell line models [196,[202][203][204][205], as well as in normal human mammary epithelial cells [206]. Conversely, cell line studies have also suggested that OSM might exert a pro-tumorigenic and prometastatic effect through induction of detachment, invasiveness, bone dissemination and EMT [160,[207][208][209]. Studies in animal models showed that OSM knockdown reduced the formation of metastases, with findings suggesting that autocrine and paracrine signalling might be linked to metastasis to bone and lungs, respectively [210,211].…”

Stimulation of Osteoclast Formation by Oncostatin M and the Role of WNT16 as a Negative Feedback Regulator

“…No formal assessment of osteoclast numbers in vivo was made, but the authors showed that OSM enhanced osteoclast formation in RANKL-stimulated cocultures of breast cancer cells and the pro-osteoclastic cell line RAW264.7, an effect that was mediated by OSMR on breast cancer cells and decreased expression of OPG. In line with these studies, it has recently been reported that OSM may play a stimulatory role in bone metastases of ER + (estrogen receptor positive) breast cancer cells in which the OSMR is more highly expressed compared to the less aggressive ER − cells [ 145 ]. In inflammatory diseases, OSM is proposed to function as a stimulator of osteoclast formation and bone loss, whereas OSM is suggested to be a stimulator of bone formation in heterotopic ossification.…”

PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR

“…This effect was further elevated when the PTHrP NLS and C-terminal domain were deleted. LIFR is known to activate STAT3, ERK, and AKT signaling, among numerous other signaling pathways in breast cancer [ 32 , 42 , 56 ]. It has been postulated that LIFR signaling promotes tumor dormancy specifically through STAT3 activation [ 32 ]; however, the oncogenic ERK and AKT pathways can still be activated by LIFR-binding cytokines [ 42 ].…”

“…LIFR is known to activate STAT3, ERK, and AKT signaling, among numerous other signaling pathways in breast cancer [ 32 , 42 , 56 ]. It has been postulated that LIFR signaling promotes tumor dormancy specifically through STAT3 activation [ 32 ]; however, the oncogenic ERK and AKT pathways can still be activated by LIFR-binding cytokines [ 42 ]. Our data here suggest that the EC359 LIFR inhibitor may preferentially decrease LIFR-mediated ERK signaling, shifting the balance towards p38 activity and suppression of cell proliferation in vitro.…”

“…Our data here suggest that the EC359 LIFR inhibitor may preferentially decrease LIFR-mediated ERK signaling, shifting the balance towards p38 activity and suppression of cell proliferation in vitro. Since LIFR activates multiple singaling pathways in breast cancer cells [ 42 ], we also sought to analyze alterations in STAT3 and AKT signaling in the presence and absence of LIFR inhibition via western blot analysis; however, activation of these pathways was too low at baseline to quantify discernable changes in pSTAT3 and pAKT.…”