Ribozyme targeting demonstrates that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen-dependent growth of human MCF-7 breast cancer cells.
Human breast tumorigenesis is promoted by the estrogen receptor pathway, and nuclear receptor coactivators are thought to participate in this process. Here we studied whether one of these coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen receptor alpha or progesterone receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen receptor coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
List
H J
HJ
Department of Oncology, Vincent T. Lombardi Cancer Center, Georgetown University, Washington, D. C. 20007, USA.
Lauritsen
K J
KJ
Reiter
R
R
Powers
C
C
Wellstein
A
A
Riegel
A T
AT
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D015536:Down-Regulation; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D056921:Nuclear Receptor Coactivator 3; D011374:Progesterone / Q000494:pharmacology; D016337:RNA, Catalytic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D004967:Estrogens; D016337:RNA, Catalytic; D012333:RNA, Messenger; D014157:Transcription Factors; D011374:Progesterone; D056921:Nuclear Receptor Coactivator 3