A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate

Br J Cancer. 2008 Oct 7;99(7):1056-63. doi: 10.1038/sj.bjc.6604634. Epub 2008 Sep 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Catechin / administration & dosage
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Catechin / therapeutic use
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1B1
  • Down-Regulation / drug effects
  • Drug Therapy, Combination
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Protein Kinases / metabolism
  • Receptors, Estrogen / metabolism*
  • TOR Serine-Threonine Kinases
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / genetics

Substances

  • Antineoplastic Agents, Hormonal
  • Receptors, Estrogen
  • Vascular Endothelial Growth Factor A
  • Tamoxifen
  • Catechin
  • epigallocatechin gallate
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cyp1b1 protein, mouse
  • Cytochrome P-450 CYP1B1
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • ErbB Receptors
  • Vascular Endothelial Growth Factor Receptor-1