Inhibition of STAT3 by 2-Methoxyestradiol suppresses M2 polarization and protumoral functions of macrophages in breast cancer

Sep 10, 2024BMC cancer

Blocking STAT3 with 2-Methoxyestradiol reduces tumor-supporting immune cells in breast cancer

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Abstract

(2ME2) reduced the expression of several anti-inflammatory cytokines and growth factors associated with .

Polarization of monocytes to M2 macrophages is linked to changes in the microtubule cytoskeleton.
At lower concentrations, 2ME2 depolymerized microtubules and inhibited the polarization of macrophages to the M2 phenotype.
2ME2 significantly reduced the expression of CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A.
Treatment with 2ME2 hindered the metastasis-promoting effects of M2 macrophages.
In an orthotopic breast cancer model, 2ME2 reduced CD163 expression in tumors and inhibited lung metastasis.
2ME2 treatment decreased the phosphorylation and nuclear translocation of STAT3, which was reversed by colivelin.

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BACKGROUND: Breast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer.

METHODS: THP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRT‒PCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo.

RESULTS: First, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin.

CONCLUSIONS: Our study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma.

Key numbers

CD163 expression reduced

Decrease in M2 Marker Expression

treatment reduced CD163 levels in tumors.

Fewer metastatic lung nodules

Lung Metastasis Reduction

-treated mice showed reduced lung metastasis compared to controls.

Inhibition of pSTAT3

STAT3 Phosphorylation Inhibition

decreased phosphorylation of STAT3 in M2 macrophages.

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Inhibition of STAT3 by 2-Methoxyestradiol suppresses M2 polarization and protumoral functions of macrophages in breast cancer

Abstract

Key numbers

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