Cancer-Preventive Rexinoid Modulates Neutral Lipid Contents of Mammary Epithelial Cells through a Peroxisome Proliferator-Activated Receptor γ-Dependent Mechanism

Abstract

Synthetic rexinoids effectively suppress both estrogen receptor-positive and estrogen receptor-negative mammary tumors in animal models, which makes them prime candidates for a novel class of cancer-preventive agents. When used in combination with chemotherapy for non-small-cell lung cancer, the rexinoid bexarotene was most effective for patients who developed hypertriglyceridemia as a side effect. Although serum triglycerides originate from the liver, the effect of bexarotene on lipogenesis in breast epithelial cells is not known. Gene expression studies with normal mammary epithelial cells indicated that rexinoids modulate lipid metabolism, particularly enzymes involved in triglyceride synthesis. High-content analysis revealed dose-dependent accumulation of neutral lipids within adipocyte differentiation-related protein-associated cytoplasmic lipid droplets after long-term bexarotene treatment. Bexarotene also induced mRNA and protein levels for peroxisome proliferator-activated receptor (PPAR) ␥, whereas selective knockdown of PPAR␥ attenuated the induction of both lipid droplets and adipocyte differentiation-related protein. Pharmacological activation of PPAR␥, but not PPAR␣ or retinoic acid receptors, effectively induced lipid accumulation. Furthermore, the combination of the PPAR␥ agonist rosiglitazone with bexarotene synergistically suppressed the growth of human mammary epithelial cells and revealed a strong, nonlinear, inverse correlation of cell growth with lipid droplet accumulation in the cell population. These findings indicate that rexinoids activate a lipogenic program in mammary epithelial cells through a retinoid X receptor/PPAR␥-mediated mechanism. It is noteworthy that combining low doses of bexarotene with the PPAR␥ agonist rosiglitazone provides effective growth suppression of mammary epithelial cells, potentially dissociating systemic adverse effects associated with standard bexarotene treatment from the antiproliferative effects on mammary epithelium.

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

“…Photoacoustic imaging of the mouse mammary tumor virus-polyoma middle T (MMTVPyMT)-driven breast cancer model demonstrated that transformation of normal breast tissue to invasive carcinoma resulted in a progressive decrease of cytoplasmic LD abundance (29). In line with this finding, pharmacological activation of peroxisome proliferatoractivated receptor-γ caused accumulation of LDs in breast cancer cells and decreased their proliferation (30). Furthermore, Src (31) and Myc (32) oncogenes were recently reported to contribute to lipid metabolism dysregulation in TNBC.…”

Yeast and cancer cells – common principles in lipid metabolism

“…A growth arrest in cells with active lipid synthesis may trigger the cells to redirect the flux of FA from membrane lipid synthesis to the synthesis of storage lipids, to avoid an accumulation of excess membranes. This hypothesis is supported by the fact that PPARγ agonists act synergistically with rexinoids [152]. However, the detailed mechanisms of rexinoid action remain to be elucidated.…”

“…Synthetic RXR ligands, also termed rexinoids, are under investigation as potent agents in therapy for several cancers. Bexarotene induces the accumulation of triacylglycerol in cytosolic lipid droplets and leads to an arrest of cell proliferation, with PPARγ agonists acting synergistically to inhibit tumor growth [152]. In cells treated with bexarotene mRNA expression of acyl-CoA synthetase 1, stearoyl-CoA dehydrogenase and diacylglycerol acyltransferase, key enzymes of FA and TAG metabolism, are induced; another important factor in lipid homeostasis, adipophilin, is elevated at the protein level upon treatment [152].…”

“…Bexarotene induces the accumulation of triacylglycerol in cytosolic lipid droplets and leads to an arrest of cell proliferation, with PPARγ agonists acting synergistically to inhibit tumor growth [152]. In cells treated with bexarotene mRNA expression of acyl-CoA synthetase 1, stearoyl-CoA dehydrogenase and diacylglycerol acyltransferase, key enzymes of FA and TAG metabolism, are induced; another important factor in lipid homeostasis, adipophilin, is elevated at the protein level upon treatment [152]. Furthermore, the authors found a strong inverse correlation between growth attenuation and neutral lipid accumulation in cancer cells, which is also observed in yeast: in a genome-wide approach to identify yeast mutants with aberrant lipid droplet morphology, strains with reduced growth rates were significantly enriched in the group of mutants with elevated lipid content [153].…”

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

“…Another approach is to examine potential enhancing interactions among the multitude of partnering nuclear hormone receptors. This way anti-proliferative and anti-tumor cooperation was demonstrated between RXRs and PPARs in premalignant mammary epithelial cells, as well as in vivo [156, 157]. …”