Activity of retinoic acid receptor-gamma selectively binding retinoids alone and in combination with interferon-gamma in breast cancer cell lines.
Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer. Retinoic acid receptor-gamma (RAR-gamma) has been shown to mediate the antiproliferative activity of retinoids. To further test this hypothesis we examined the effects of different RAR-gamma selectively binding retinoids (CD2325, CD2247, CD666 and CD437) on breast cancer cell lines. With exception of CD2247, all retinoids inhibited proliferation of MCF-7, SKBR-3, T47D and ZR-75-1 breast cancer cell lines, similar to the natural compound all-trans retinoic acid (ATRA). In addition, all 4 compounds were able to act synergistically with interferon-gamma (IFN-gamma) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines. In functional transactivation assays we demonstrated that only in the MCF-7 cell line, TPA-mediated AP-1 activity was suppressed only by ATRA and CD2325, whereas in SKBR-3, another RA-sensitive breast cancer cell line, it was not. The synergistic antiproliferative activity involving retinoids and IFN-gamma could not be explained by an enhanced anti-AP-1 activity. No correlation was found between expression of RARs and cellular retinoic acid binding proteins (CRABPs) and antiproliferative effects of the retinoids. RAR-gamma selectively binding retinoids are potent inhibitors of breast cancer cell proliferation, alone and in combination with IFN-gamma. For this reason and because of a possible low toxicity, as compared with retinoic acid, we speculate that these RAR-gamma selective binding retinoids might be of clinical importance.
Widschwendter
M
M
Department of Obstetrics and Gynecology, University of Innsbruck, Austria.
Daxenbichler
G
G
Culig
Z
Z
Michel
S
S
Zeimet
A G
AG
Mörtl
M G
MG
Widschwendter
A
A
Marth
C
C
D001667:Binding, Competitive; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
D015500:Chloramphenicol O-Acetyltransferase; D007371:Interferon-gamma; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012176:Retinoids; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437; C082927:retinoic acid binding protein I, cellular; C082928:retinoic acid binding protein II, cellular