An in vivo model of intratumoural aromatase using aromatase-transfected MCF7 human breast cancer cells.
About two-thirds of human breast carcinomas contain detectable levels of aromatase, the enzyme which converts androgens to oestrogens. Assessment of the importance of this enzyme to breast cancer growth has been hampered by the absence of an adequate model system. We have previously reported that MCF7 human hormone-dependent breast cancer cells transfected with human aromatase cDNA (Arom1 cells) showed a growth response in vitro to exogenous androgens and this effect was blocked by aromatase inhibitors. We report here our use of these cells to develop a xenograft model in athymic nude mice. Neither MCF7 cells nor Arom1 cells formed tumours in oophorectomised (ovx) nude mice unless provided with oestradiol (E2) support. Once established, Arom1, but not MCF7, tumours could be grown in ovx females supplemented with androstenedione (delta 4A). The mean plasma level of delta 4A was 14 nmol/L in supplemented animals and < 0.5 nmol/L in unsupplemented animals. Similarly, unsupplemented male nude mice were able to support the growth of Arom1 tumours but not MCF7 tumours. The potent and highly specific aromatase inhibitor CGS20267 (letrozole) significantly decreased tumour growth at 2 mg/kg/day and completely inhibited growth at 20 mg/kg/day in delta 4A-supplemented but not E2-supplemented animals. Our results indicate that delta 4A-dependent growth of Arom1 tumours in vivo is mediated through the action of intratumoural aromatase. This model should allow an assessment of the critical levels of aromatase required for tumour growth support.
Lee
K
K
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
Macaulay
V M
VM
Nicholls
J E
JE
Detre
S
S
Ashworth
A
A
Dowsett
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D000077289:Letrozole; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D014162:Transfection; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase