Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors.
Although the antiestrogen tamoxifen has been the mainstay of therapy for estrogen receptor (ER)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxifen resistance. Subsequently, only 30-40% of patients have a positive response to second hormonal therapies. This lack of response might be explained by mechanisms for tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic activity present in tamoxifen or that bypass ER pathways completely. To elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen ICI 182,780 or one of two aromatase inhibitors, 4-OHA or letrozole. These treatments did not slow estrogen-independent growth or prevent metastasis of tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice. FGF-transfected cells had diminished responses to ICI 182,780 in vitro, suggesting that autocrine activity of the transfected FGF may be replacing estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF transfectants were not down-regulated, and basal levels of transcripts for estrogen-induced genes or of ER-mediated transcription of estrogen response element (ERE) luciferase reporter constructs in the FGF expressing cells were not higher than parental cells, implying that altered hormonal responses are not due to down-regulation of ER or to FGF-mediated activation of ER. These studies indicate that estrogen independence may be achieved through FGF signaling pathways independent of ER pathways. If so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of antiestrogen treatment.
McLeskey
S W
SW
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Zhang
L
L
El-Ashry
D
D
Trock
B J
BJ
Lopez
C A
CA
Kharbanda
S
S
Tobias
C A
CA
Lorant
L A
LA
Hannum
R S
RS
Dickson
R B
RB
Kern
F G
FG
D000735:Androstenedione / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use / Q000633:toxicity; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D004965:Estrogen Antagonists / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D000077267:Fulvestrant; D006801:Humans; D000077289:Letrozole; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000627:therapeutic use / Q000633:toxicity; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013629:Tamoxifen / Q000627:therapeutic use* / Q000633:toxicity; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000627:therapeutic use / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D009570:Nitriles; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D000735:Androstenedione; D004958:Estradiol; D005346:Fibroblast Growth Factors; D000077289:Letrozole; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; C014594:formestane