Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling

Table 1

Treatments or interventions targeting or affecting IL-1 signaling in breast cancer.

Treatment/intervention	Targets	In vivo/in vitro	Models	Findings	References
Anakinra; anti-TGFβ	IL-1R1	In vivo	Hs578T; NOD/SCID/β2m^−/−; patients with HER2 metastatic BC (NCT01802970)	Prevented tumor progression and production of IL-13 in humanized mouse model; downregulated specific components of the systemic inflammatory signature observed in patients with metastatic BC and rescued cytotoxic programs thought to be critical for antitumor activity	[81]
Anti-IL-1R; anakinra	IL-1 signaling	In vivo	4T1; E0771; BALB/c; C57BL/6	Reduced tumor progression and production of IL-22^+ cells	[83]
IL1Ra; caspase-1 inhibitor; Ac-YVAD-cmk; anti-IL-1β; anticaspase-1; caspase-1^−/−; NLRP3^−/−	IL-1 signaling	In vivo and in vitro	EO771; PyT8; MDA-MB-231; C57BL/6J; NSG; MMTV-PyMT	Reduced tumor growth and lung metastasis accompanied by decreased myeloid cell accumulation	[84]
Anti-CD44	CD44	In vitro	MDA-MB231; MDA-MB-468; MCF-7; MCF-10A; 4T1-Luc; THP-1; human serum samples; BALB/c	Abrogated IL1β production in macrophages and inhibited growth of primary tumors	[86]
IRAK1 inhibitor synergized with either cisplatin or paclitaxel	IL-1α signaling	In vivo	FVB/N	Reduction of CSCs and improvement of the chemotherapy efficacy	[87]
Anti-IL-1R1; anakinra; caspase 1/11^−/−; NLRP3^−/−; NLRC4^−/−	NLRC4/IL-1β	In vivo	Py8119; E0771; C57BL/6N	Reduced tumor growth except NLRP3^−/− mice	[88]
Anti-IL-1β, anti-PD-1	IL-1β, PD-1	In vivo	4T1; BALB/c	Anti-IL-1β Abs and anti-PD-1 Abs have a synergistic antitumor activity	[91]
IL-1R8^−/−	IL-1R8	In vivo and in vitro	HB4a; HB4a-C5.2; NKL; THP-1; MMTV-neu	Reduced tumor growth and metastasis	[92]
IL-1Ra; Bay; Zerumbone	NF-κB signaling pathway	In vitro	Hs578T; MDA-MB231	Inhibition of IL-1β expression and cell invasiveness	[95]
Anakinra	IL-1R1	In vivo	MSCs; IRISOE cell lines; SCID	Decreased recruitment of mouse MSCs into IRISOE-TNBC tumors and their activation to produce and secrete CXCL1	[100]
IL-1Ra	IL-1R1	In vitro	MDA-MB-231 and UC-MSCs coculturing system	Blocked prostemness effects of UC-MSCs on cancer cells	[103]
Anakinra	IL-1R1	In vivo and in vitro	T47D; MCF-7; BB3RC32; BB2RC08; BB6RC37	Reduced bone metastasis	[112]
Sulfasalazine; KG-501	NF-κB; CREB	In vitro	MCF-7; MDA-MB-231_BH	Inhibited Wnt-dependent CSC colony formation in the bone environment	[113]
Anti-IL-1β	IL-1β	In vivo	NSG	Reduced tumor formation; increased trabecular bone volume
IL-1Ra; canakinumab	IL-1β signaling	In vivo	MDA-MB-231; E0771; NOD/SCID; BALB/c nude	Reduced spontaneous metastasis to human bone	[114]
Caspase-1 inhibitor	Caspase-1	In vitro	MDA-MB-231	Abrogated level of transmigration of MDA-MB-231 cells through both blood and lymphatic endothelial cell barriers
Verteporfin; siRNA-silenced p62	SQSTM1/p62	In vitro	MCF-7; MDA-MB-231	Cytotoxic for HR- cell lines	[52]
IRAK1/4 inhibitor; BAY11-7082; SP600125; and LY294002	NF-κB, JNK, PI3K	In vitro	MCF-7 (ATCCHTB-22); MCF-7_TG2	Inhibited expression of IL-6 from IL-1β-stimulated TG2-overexpressing MCF-7_TG2 BC cells	[123]
Anakinra	IL-1R1	In vivo	MDA-MB-231-IV or MCF-7; BALB/c	Reduced growth of tumors in bone and the number of mice that developed bone metastases	[138]
scFv 12H7	IL-1RAcP	In vivo and in vitro	Patients; MDA-MB-231; HCC-70	Increased expression of IL-1RAcP in both TNBC cell lines and TNBC patient cohort; scFv 12H7 inhibited tumor growth via inhibiting IL-1-activated-NF-κB pathway in TNBC cells	[139]
miR-146a-5p	IRAK1	In vitro	MDA-MB-453; MCF-7	Repressive effects on the proliferation and invasion behavior of BC cells by targeting IRAK1	[143]
CAR-T therapy and IL-37	IL-1, IL-33			Inhibited inflammation and toxicity generated in tumor CAR-T therapy	[144]

Notes. ^−/−Symbols indicate that the gene has been knocked out. Abbreviations: CSC—cancer stem cell; MSC—mesenchymal stem cell; NLRP3—NOD-like receptor family pyrin domain domain-containing protein 3; CREB—cyclic AMP response-element binding protein; IRAK1—interleukin-1 receptor-associated kinase 1; TG2—transglutaminase 2; CAR-T—chimeric antigen receptor T cell.