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) γ, whereas selective knockdown of PPARγ attenuated the induction of both lipid droplets and adipocyte differentiation-related protein. Pharmacological activation of PPARγ, but not PPARα or retinoic acid receptors, effectively induced lipid accumulation. Furthermore, the combination of the PPARγ 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/PPARγ-mediated mechanism. It is noteworthy that combining low doses of bexarotene with the PPARγ 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.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant R03-CA137777] (to I.P.U. and M.A.M.), [Grant R01-CA78480] (to P.H.B.); and in part by seed funding from the Hankamer Foundation (to M.A.M.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- HMEC
- human mammary epithelial cell
- PPAR
- peroxisome proliferator-activated receptor
- RXR
- retinoid X receptor
- ER
- estrogen receptor
- DAPI
- 4′,6-diamidino-2-phenylindole
- siRNA
- small interfering RNA
- SCD1
- stearoyl-CoA desaturase 1
- ACSL1
- acyl-CoA synthetase 1
- DGAT1
- diacylglycerol acyl-transferase 1
- ADFP
- adipocyte differentiation-related protein
- LXR
- liver X receptor
- RT
- reverse transcription
- NA
- numerical aperture
- PCR
- polymerase chain reaction.
- Received April 17, 2011.
- Accepted October 28, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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