A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate.
We have previously shown that tamoxifen+epigallocatechin gallate (EGCG) is synergistically cytotoxic towards oestrogen receptor (ER)-negative breast cancer cells. To determine if this response would correlate with significant tumour suppression in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with tamoxifen, EGCG, EGCG+tamoxifen, or vehicle control for 10 weeks. Tumour volume in EGCG- (25 mg kg(-1))+tamoxifen (75 microg kg(-1))-treated mice decreased by 71% as compared with vehicle control (P<0.05), whereas tumour weight was decreased by 80% compared with control (P<0.01). Epigallocatechin gallate treatment did not alter ER protein expression in MDA-MB-231 cells and thus was not a mechanism for the observed tumour suppression. However, western blotting of tumour extracts demonstrated that epidermal growth factor receptor (EGFR; 85% lower than control), pEGFR (78% lower than control), mammalian target of rapamycin (mTOR; 78% lower than control), and CYP1B1 (75% lower than control) were significantly lower after the combination treatment as compared with all other treatments. Nuclear factor-kappaB (NF-kappaB), b-Raf, p-MEK, S6K, 4EBP1, Akt, vascular EGFR-1 (VEGFR-1) and VEGF expressions were decreased in control but not in the individual treatments, whereas MEK, phospholipase D 1/2, TGF alpha, and ERK expressions were not changed after any treatment. The results demonstrate that tamoxifen at realistic doses (75 mug kg(-1)) can suppress the growth of ER-negative breast cancer when combined with EGCG. In addition, the dominant mechanism for tumour suppression is the concomitant decrease in tumour protein expressions of mTOR and the EGFR.
Scandlyn
M J
MJ
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
Stuart
E C
EC
Somers-Edgar
T J
TJ
Menzies
A R
AR
Rosengren
R J
RJ
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D002392:Catechin; C045651:epigallocatechin gallate; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D040281:Vascular Endothelial Growth Factor Receptor-1; D058570:TOR Serine-Threonine Kinases
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