IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis

Abstract

A variety of osteolytic factors have been identified from breast cancer cells leading to osteolysis, but less is known about which factor plays an essential role in the initiation process prior to the overt vicious osteolytic cycle. Here, we present in vitro and in vivo evidences to clarify the role of interleukin-11 (IL-11) as an essential contributor to breast cancer bone metastasis mediated osteolysis. Animal studies showed that bone specific metastatic BoM-1833 cells induce earlier onset of osteolysis and faster tumor growth compared with MCF7 and parental MDA-MB-231 cells in BALB/c-nu/nu nude mice. IL-11 was further screened and identified as the indispensable factor secreted by BoM-1833 cells inducing osteoclastogenesis independently of receptor activator of nuclear factor κB ligand (RANKL). Mechanistic investigation revealed that the JAK1/STAT3 signaling pathway as a downstream effector of IL-11, STAT3 activation further induces the expression of c-Myc, a necessary factor required for osteoclastogenesis. By inhibiting STAT3 phosphorylation, AG-490 was shown effective in reducing osteolysis and tumor growth in the metastatic niche. Overall, our results revealed the essential role and the underlying molecular mechanism of IL-11 in breast cancer bone metastasis mediated osteolysis. STAT3 targeting through AG-490 is a potential therapeutic strategy for mitigating osteolysis and tumor growth of bone metastatic breast cancer.

Role of STAT3 signaling pathway in breast cancer

“…miR-30d is found to mediate migration and invasion in breast cancer cells by regulating Krüppel-like factor 11 (KLF-11), a new exogenous signaling pathway that can activate STAT3 by binding to its transmembrane receptor KLF-11R [54]. In addition, IL-11 is also found to regulate the JAK/STAT3 pathway in breast cancer-bone metastasis [55]. PIM1, a proto-oncogene responsible for promoting cell invasion and upregulating EMT expression in breast cancer, is found to be regulated by the IL-6/STAT3 signaling pathway [56].…”

The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis

“…Breast cancer with bone metastasis shows significantly increased expression of IL-11 in comparison with breast cancer without bone metastasis, and IL-11 is known to be involved in bone metastasis through the gp130/STAT3 pathway [ 51 ]. IL-11, secreted from the bone-specific metastatic breast cancer cell line (BoM-1833), promotes osteolytic bone metastasis by activating RANKL-independent osteoclastogenesis through the JAK1/STAT3 pathway [ 52 ]. Insulin-like growth factor-binding protein 2 (IGFBP2), secreted by metastatic breast cancer cells, contributes to metastatic bone colonization by interacting with IGF type-1 receptor on endothelial cells through endothelial recruitment [ 56 ].…”

Gut microbiota regulate tumor metastasis via circRNA/miRNA networks

“…56 IL-11 is also essential in promoting osteolysis in breast cancer bone metastasis. 57 Thus, it is likely that IL-11 release may serve as the first step after dysbiosis of the gut microbiome, followed by activation of the SOX9 in ABX or GF mice. Therefore, there is a mechanistic link between the gut microbiota and cancer metastasis through the IL-11/circRNA/miRNA axis.…”