Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy

Abstract

Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…191 Potential mechanisms of action include FXR-mediated inhibition of leptin-induced oncogenic cancer-associated fibroblasts (CAFs) in multiple BC cell lines by increasing suppressor of the cytokine signaling 3 (SOCS3) expression downstream of FXR-implicating an obesity-specific susceptibility. 188 SOCS3 is downregulated in BC. 192 FXR may also mediate tumor effects through destabilization of hypoxia-inducible factor-1 alpha (HIF1-α), a master regulator that reprograms cancer cell metabolism and increases growth factors.…”

“…187 Activation of FXR by BA endogenous ligand CDCA or synthetic FXR agonist GW4046 induced apoptosis in normal and malignant BC cells of various BC subtypes and reduced MCF-7 xenograft growth. 188,189 High FXR associated with smaller tumor size, high proliferation rate, relapse-free survival, distant metastasis-free survival, and overall survival in BC patients. 190,191 Indeed, FXR is an independent prognostic factor for overall and disease-free patients' survival.…”

The potential role of leptin in tumor invasion and metastasis

“…In fact, cancer cells and CAFs crosstalk enhances the production of growth factors, cytokines, chemokines, MMPs, and inflammatory mediators, which eventually facilitates tumor growth [3]. Interestingly, leptin has been demonstrated to be closely associated with activities of CAFs and expression levels of MMPs [5–7]. On the other hand, many reports have revealed leptin’s link with a number of ECM components such as fibronectin, transforming growth factor-beta (TGF-β), and connective tissue growth factor (CTGF) as well as several intracellular signaling molecules including AKT, phosphatidylinositol 3-kinase (PI3K), and signal transducer and activator of transcription (STAT) [8–10].…”

Exploiting vulnerabilities of cancer by targeting nuclear receptors of stromal cells in tumor microenvironment

“…Loss of function of FXR is strongly linked to carcinogenesis in the liver, intestines and colorectal region where the receptor is highly expressed [ 75 , 76 ]. Interestingly, in breast cancer cells exposed to the FXR agonist GW4064, conditioned medium from CAFs fail to promote enhanced growth, motility, and invasiveness [ 77 ]. This observation reflects a neutralizing effect of FXR activation on the tumorigenic paracrine signaling conferred by CAFs.…”

“… • GW4064-treated tumors had smaller sizes in in vivo xenograft studies. [ 77 ] CAF Breast cancer Cell culture FXR Agonist – GW4064 • GW4064 reduced migration and contractility of CAFs besides inhibiting growth and motility of cancer cells. [ 78 ] CAF Breast cancer RARβ knockout mice RARβ RARβ gene knockout • RARβ knockout mice had reduced angiogenesis, inflammatory cell infiltration and myofibroblast count.…”