An in vivo model of intratumoural aromatase using aromatase‐transfected MCF7 human breast cancer cells

Abstract

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.

Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In vivo

“…These cells, when injected s.c. into immunocompromised mice, form tumors under androstenedione support (20). MCF7 AROM 1 cells convert androstenedione to estradiol providing an intratumoral source of estrogen representative of postmenopausal, hormone-dependent breast cancer.…”

Pre-clinical validation of early molecular markers of sensitivity to aromatase inhibitors in a mouse model of post-menopausal hormone-sensitive breast cancer

“…We present pre-clinical results on novel candidates for clinical development as markers of ER dependent pathway activation and endocrine treatment efficacy. We have performed this study using an animal model that has been shown to predict the behaviour of human ER positive breast cancer when exposed to aromatase inhibitors [22,21]. Extrapolation of our results to human tumours demands great caution given the expected differences between both settings.…”

“…Pellets containing 60-day release of 15 mg androstenedione (Innovative Research of America Ò ) were inserted subcutaneously at the same time but in a distant site from tumour cells implant. MCF-7 cells transfected with the aromatase gene (MCF-7 Arom1 cells) [21] were grown to 80% confluence in DMEM culture medium containing 10% FCS, 1% penicillin and streptomicin, 2 mM glutamine, 1 mM sodium pyruvate, 10 lg/ ml insulin and 600 lg/ml G418 to maintain selection for neomycin-resistant cells. Cells were scraped and resuspended in matrigel.…”

“…To do so we have used a well established animal model for aromatase inhibitor sensitive breast cancer [22,21]. We also explored whether determination of these genes is feasible using minimally invasive techniques (fine needle aspirates).…”

“…Briefly, core biopsies were taken from postmenopausal patients diagnosed with localized breast cancer before and after two weeks of treatment with either anastrozole or letrozole. Messenger RNA was obtained and hybridized onto cDNA microarrays to screen for those genes significantly regulated by these drugs that produce a highly effective abolition of circulating and intratumoral oestradiol in the postmenopausal woman [21].…”