The role of IL-1B in breast cancer bone metastasis

Abstract

Approximately 75% of patients with late-stage breast cancer will develop bone metastasis. This condition is currently considered incurable and patients' life expectancy is limited to 2-3 years following diagnosis of bone involvement. Interleukin (IL)-1B is a pro-inflammatory cytokine whose expression in primary tumours has been identified as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In this review, we discuss how IL-1B from both the tumour cells and the tumour microenvironment influence growth of primary breast tumours, dissemination into the bone metastatic niche and proliferation into overt metastases. Recent evidence indicates that targeting IL-1B signalling may provide promising new treatments that can hold tumour cells in a dormant state within bone thus preventing formation of overt bone metastases.

Keywords: IL-1B; bone metastasis; breast cancer.

Figure 1

Vicious cycle and dormancy. Bone is a favourite site for metastatic breast cancer. Tumour cells arriving in bone undergo dormancy. Osteoclasts and osteoblasts secrete factors to maintain bone homeostasis (factors released by osteoblasts and osteoclasts are indicated in orange and purple, respectively). Bone remodelling cytokines stimulate tumour cells that, after homing in bone, have entered a dormant state. Simultaneously, tumour cells produce factors (in grey) that stimulate further osteoblasts and osteoclasts activity, resulting in awakening cancer cells with the formation of overt bone metastases and altered bone turnover. This vicious cycle leads to enhanced tumour cell proliferation and aggressiveness, increased osteoclast number and activity and decreased osteoblast number and function, resulting in osteolytic bone metastases. We hypothesise that IL-1B is a putative factor exchanged between tumour cells, osteoblasts and osteoclasts, and a trigger for tumour cells awakening from dormancy and formation of bone metastasis.

Figure 2

IL-1B signalling. IL-1B is produced as pro-peptide and activated by cleavage upon cell stimulation by PAMPs and DAMPs, as response mechanism to invading pathogens and cellular stress caused by sterile danger signals. IL-1B is functionally activated upon cleavage by caspase-1, which in turn, is activated by the NLRP3 inflammasome complex. After cleavage and activation, IL-1B is released by the cell, according to a poorly understood mechanism that comprehends both active and passive processes, including pyroptosis. Once released, IL-1B activates IL-1R1 receptor. Downstream signalling activation through Myd88, IRAKs and TRAF6 leads to NFKB-mediated transcription of pro-inflammatory cytokines and initiation of inflammation.

Figure 3

IL-1 signalling in breast primary tumour and bone metastasis. IL-1 signalling controls breast cancer growth at both primary and bone metastatic sites. Osteotrophic breast cancer cells MDA-231-IV or ER+ breast tumour cells MCF-7 are implanted subcutaneously in BALB/c-nude mice to mimic primary tumour growth. IL-1 signalling inhibition using the receptor antagonist Anakinra results in reduced tumour growth as well as diminished tumour microvessel density. Upon i.v. injection, MDA-231-IV cells home to bone. Anakinra treatment affects metastatic breast cancer tumour growth, without altering the number of cells homing to this site, suggesting the involvement of IL-1 signalling in breast cancer dormancy in bone.