The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling.
Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERalpha and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERalpha transactivation, expression of ERalpha, ERbeta and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERalpha levels whilst having no effect on ERbeta expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERalpha expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERalpha, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor.
Martin
L-A
LA
Academic Department of Biochemistry, Institute of Cancer Research, London, UK. lesley-ann.martin@icr.ac.uk
Pancholi
S
S
Chan
C M W
CM
Farmer
I
I
Kimberley
C
C
Dowsett
M
M
Johnston
S R D
SR
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000172:deficiency; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C526297:IRS2 protein, human; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D017526:Receptor, IGF Type 1