A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands.
BACKGROUND
Certain lipids have been shown to be ligands for a subgroup of the nuclear hormone receptor superfamily known as the peroxisome proliferator-activated receptors (PPARs). Ligands for these transcription factors have been used in experimental cancer therapies. PPARs heterodimerize and bind DNA with retinoid X receptors (RXRs), which have homology to other members of the nuclear receptor superfamily. Retinoids have been found to be effective in treating many types of cancer. However, many breast cancers become resistant to the chemotherapeutic effects of these drugs. Recently, RXR-selective ligands were discovered that inhibited proliferation of all-trans retinoic acid resistant breast cancer cells in vitro and caused regression of the disease in animal models. There are few published studies on the efficacy of combined therapy using PPAR and RXR ligands for breast cancer prevention or treatment.


METHODS
We determined the effects of selective PPAR and RXR ligands on established human breast cancer cell lines in vitro.


RESULTS
PPAR-alpha and PPAR-gamma ligands induced apoptotic and antiproliferative responses in human breast cancer cell lines, respectively, which were associated with specific changes in gene expression. These responses were potentiated by the RXR-selective ligand AGN194204. Interestingly, RXR-alpha-overexpressing retinoic acid resistant breast cancer cell lines were more sensitive to the effects of the RXR-selective compound.


CONCLUSIONS
RXR-selective retinoids can potentiate the antiproliferative and apoptotic responses of breast cancer cell lines to PPAR ligands.
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California, USA. dcrowe@usc.edu
David L
DL
Crowe
Roshantha A S
RA
Chandraratna
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D017965:gamma-Linolenic Acid / Q000494:pharmacology
C430898:AGN 194204; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014212:Tretinoin; D017965:gamma-Linolenic Acid