A pure antiestrogen, ICI 182,780, stimulates the growth of tamoxifen-resistant KPL-1 human breast cancer cells in vivo but not in vitro.
The critical mechanisms responsible for antiestrogen resistance have not yet been elucidated. We previously established a breast cancer cell line, KPL-1, derived from a patient with recurrent disease which appeared under tamoxifenadministration. In a previous study, we suggested that this cell line is estrogen receptor (ER)-positive but tamoxifen-resistant. In the present study, the effects of a pure antiestrogen, ICI 182,780, on this cell line were investigated. Although tamoxifen inhibited neither cell growth nor estradiol-stimulated transcriptional activity in vitro, ICI 182,780, significantly inhibited both of them. Tamoxifen and ICI 182,780 were then administered to female nude mice bearing KPL-1 tumors. Tamoxifen had no effect on tumor growth, but ICI 182,780 unexpectedly stimulated it (p = 0.022). Estradiol tended to inhibit tumor growth (p = 0.198). Immunohistochemical analysis revealed that ICI 182,780 significantly increased the Ki6-labeling index (p<0.001) but estradiol decreased it (p = 0.035). To explore the possible mechanisms of these phenotypes, the mRNA levels of ER-alpha,ER-beta, transforming growth factor-beta1, fibroblast growth factor (FGF)-1 and FGF-4 in KPL-1 cells were compared with those in other ER-positive human breast cancer cell lines by reverse-transcription polymerase chain reaction. FGF-1 was overexpressed only in KPL-1 cells. This cell line is the first breast cancer cell line to be growth-stimulated by ICI 182,780 in vivo. Paracrine interaction between tumor cells and stromal cells mediated by growth factors, such as FGF-1, might be a key factor to explain the unique hormone responsiveness of KPL-1 cells.
Kurebayashi
J
J
Department of Breast and Thyroid Surgery, Okayama, Japan. kure@med.kawasaki-m.ac.jp
Otsuki
T
T
Yamamoto
S
S
Kurosumi
M
M
Nakata
T
T
Akinaga
S
S
Sonoo
H
H
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005346:Fibroblast Growth Factors / Q000187:drug effects; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D012334:RNA, Neoplasm / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D005346:Fibroblast Growth Factors