Docosahexaenoic acid induces proteasome-dependent degradation of estrogen receptor alpha and inhibits the downstream signaling target in MCF-7 breast cancer cells.
About two thirds of breast cancers in women are hormone-dependent and require estrogen for growth, its effects being mainly mediated through estrogen receptor alpha (ERalpha). Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) have opposite effects on carcinogenesis, with DHA suppressing and AA promoting tumor growth both in vitro and in vivo. However, the mechanism is not clear. Here, we examined whether the effect is mediated through changes in ERalpha distribution. MCF-7 cells, an ERalpha-positive human breast cancer cell line, was cultured in estrogen-free medium containing 0, 10 or 60 microM DHA or AA, then were stimulated with estradiol. DHA supplementation resulted in down-regulation of ERalpha expression (particularly in the extranuclear fraction), a reduction in phosphorylated MAPK, a decrease in cyclin D1 levels and an inhibition in cell viability. In contrast, AA had no such effects. The DHA-induced decrease in ERalpha expression resulted from proteasome-dependent degradation and not from decreased ERalpha mRNA expression. We propose that breast cancer cell proliferation is inhibited by DHA through proteasome-dependent degradation of ERalpha, reduced cyclin D1 expression and inhibition of MAPK signaling.
Lu
I-Fen
IF
Department of Physiology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Hasio
Ann-Che
AC
Hu
Meng-Chun
MC
Yang
Feng-Ming
FM
Su
Hui-Min
HM
D000418:Albumins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D019938:Cyclin D1 / Q000096:biosynthesis; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
D000418:Albumins; D047628:Estrogen Receptor alpha; D019938:Cyclin D1; D004281:Docosahexaenoic Acids; D004958:Estradiol; D046988:Proteasome Endopeptidase Complex