HIGH expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1β

Abstract

Chronic inflammation has been recognized as a risk factor for the development and maintenance of malignant disease. Cytokines such as interleukin-6 (IL-6), oncostatin M (OSM), and interleukin-1 beta (IL-1β) promote the development of both acute and chronic inflammation while promoting in vitro metrics of breast cancer metastasis. However, anti-IL-6 and anti-IL-1β therapeutics have not yielded significant results against solid tumors in clinical trials. Here we show that these three cytokines are interrelated in expression. Using the Curtis TCGA™ dataset, we have determined that there is a correlation between expression levels of OSM, IL-6, and IL-1β and reduced breast cancer patient survival ( r = 0.6, p = 2.2 x 10 −23 ). Importantly, we confirm that OSM induces at least a 4-fold increase in IL-6 production from estrogen receptor-negative (ER−) breast cancer cells in a manner that is dependent on STAT3 signaling. Furthermore, OSM induces STAT3 phosphorylation and IL-1β promotes p65 phosphorylation to synergistically induce IL-6 secretion in ER− MDA-MB-231 and to a lesser extent in ER+ MCF7 human breast cancer cells. Induction may be reduced in the ER+ MCF7 cells due to a previously known suppressive interaction between ER and STAT3. Interestingly, we show in MCF7 cells that ER’s interaction with STAT3 is reduced by 50% through both OSM and IL-1β treatment, suggesting a role for ER in mitigating STAT3-mediated inflammatory cascades. Here, we provide a rationale for a breast cancer treatment regime that simultaneously suppresses multiple targets, as these cytokines possess many overlapping functions that increase metastasis and worsen patient survival.

Identification the prognostic value of immune gene signature and infiltrating immune cells of esophageal cancer patients

“…OSM (oncostatin M) was involved in tumor development and insulin resistance [43]. It has been reported that OSM as a risk factor promote breast cancer metastasis [44]. Studies indicated that the expression of NR2F2 (Nuclear receptor subfamily 2) are associated with survival outcome in gastric cancer [45] and breast cancer [46].…”

Role of STAT3 signaling pathway in breast cancer

“…2. A member of the IL-6 family of cytokines, Oncostatin M (OSM) can induce IL-6 upregulation and STAT3 phosphorylation to promote breast cancer progression [13] and to activate STAT3 and hypoxia inducible factor 1 alpha (HIF-1α) in estrogen receptor (ER)-breast cancer cells or in ER+ breast cancer cells in cooperation with IL-6 [14]. Additionally, other interleukins, such as IL-35 and IL-8, are also found to promote breast cancer progression by activating STAT3.…”

GP130 Cytokines in Breast Cancer and Bone

“…In the presence of OSM, T47D cells exhibited decreased intercellular contact [122], and increased cellular detachment and invasiveness [123]. In patient data, high OSM expression has also been correlated with decreased patient survival, pointing to its possible role in metastatic disease [124]. In the context of breast cancer bone metastasis, one group has shown that OSM knockdown in 4T1 mouse mammary carcinoma cells reduced spontaneous metastasis to the spine, as assessed by qPCR analysis following orthotopic injections, and less osteolytic bone destruction following intratibial injections [125].…”

“…Activation of downstream signaling by the gp130 family: Upon binding to gp130 and their cytokine-specific receptor on tumor cells, the gp130 ligands are known to activate the JAK/STAT, MAPK/MEK/ERK, and PI3K/AKT signaling pathways [20][21][22][23]. While there has not been a comprehensive comparison of the downstream pathways activated by each ligand in breast cancer, many mechanistic studies have identified STAT3 as the key downstream mediator of IL-6 [127] and OSM [124,128,129] tumor-promoting effects. Signal transduction by IL-6, LIF, and OSM is initiated after dimer formation between the cytokine specific receptors (e.g., IL-6R, LIFR, and OSMR) and gp130, resulting in the phosphorylation of STAT3 by JAK [16,130,131].…”

“…This study also noted that several gp130 cytokines (IL-6, LIF, CT-1, and CNTF) were able to significantly increase the CSC population in HMECs, pointing to their potential role as microenvironmental cytokines capable of promoting tumor progression through STAT3. OSM has also been shown to induce IL-6 in a STAT3-dependent manner in ER-breast cancer cells [124].…”