Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment

Abstract

Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility.

A therapeutic antibody targeting annexin-A1 inhibits cancer cell growth in vitro and in vivo

“…However, in addition to the well-documented role in immunity, there is significant evidence that ANXA1 is an important component of several upstream signalling pathways in a number of diseases [ 31 ]. In the context of cancer, ANXA1 has been shown to be involved in STAT3 [ 32 ], PI3K [ 33 ] and MAPK/ERK [ 11 ] signalling pathways which promote tumour initiation and progression.…”

A therapeutic antibody targeting annexin-A1 inhibits cancer cell growth in vitro and in vivo.

“…However, in addition to the well documented role in immunity, there is signi cant evidence that ANXA1 is an important component of several upstream signalling pathways in a number of diseases (33). In the context of cancer, ANXA1 has been shown to be involved in STAT3 (34), PI3K (35) and MAPK/ERK (11) signalling pathways which promote tumour initiation and progression.…”

Expression profile of interleukin-6, 4-hydroxy-2-nonenal, and hypoxia-inducible factor 1-α in women with breast cancer and their association with clinicopathological parameters

“…[ 46 ] report that intact IL-6 signaling in T cells is important for controlling cancer progression and that IL-6 signaling in peripheral blood T cells at diagnosis is considered as a predictive biomarker for clinical result in BC. Vecchi et al [ 47 ] found that IL-6 expression was lower in BC samples classified as N1 and N2 and high in N0 samples.…”

“…Vecchi et al . [ 47 ] showed that IL-6 expression is elevated in triple-negative BC (TNBC), and weakly and moderately expressed in the other subtypes (luminal A, luminal B, and HER2+). Another in vitro study by Pe et al .…”