Conjugated linoleic acid blocks estrogen signaling in human breast cancer cells.
Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid found in dairy products and meat from ruminants, has been widely shown to possess anticarcinogenic activity against breast cancer both in vitro and in animal models. However, little information is available concerning the mechanisms of the antitumor effects of these compounds. In this study, we investigated whether CLA has direct antiestrogenic activity in estrogen receptor positive (ER+) breast cancer cells. Treatment of the ER+ cell line, MCF-7, with 5 purified CLA isomers as well as "mixed" CLA showed a dose-dependent growth inhibition with the 9cis,11cis and 9cis,11trans being the most and least potent isomers, respectively. In assessing effects on a number of variables that play obligatory roles in the estrogen signaling pathway, we determined that CLA treatment downregulated ERalpha expression at both mRNA and protein levels and decreased binding activity of nuclear protein to a canonical estrogen response element (ERE(v)). Using a reporter gene construct (ERE(v)-tk-Luc) that was transiently transfected into MCF-7 cells, we also demonstrated inhibition of promoter activity by CLA that was directly mediated by blockage of activity through the ERE. The results indicated that the order of potency of the CLA isomers for inhibiting activation of ERE(v) was similar to that demonstrated for their antiproliferative activity on MCF-7 cells. Taken together, these findings demonstrate that CLA compounds possess potent antiestrogenic properties that may at least partly account for their antitumor activity on breast cancer cells.
Division of Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Prasong
P
Tanmahasamut
Jingbo
J
Liu
Lawrence B
LB
Hendry
Neil
N
Sidell
D000199:Actins / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000199:Actins; D017931:DNA Primers; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D044243:Linoleic Acids, Conjugated; D011960:Receptors, Estrogen