A novel in vitro and in vivo breast cancer model for testing inhibitors of estrogen biosynthesis and its action using mammary tumor cells with an activated int-5/aromatase gene.
We recently showed that the cellular gene int-5/aromatase in BALB/c mammary alveolar hyperplastic nodule (D2 HAN/D2 tumor cells) is activated as a result of mouse mammary tumor virus integration within the 3' untranslated region of the aromatase gene. In the present study, we evaluated the effect of various aromatase inhibitors on androstenedione-mediated tumor cell growth. Also, we compared the effect of the non-steroidal aromatase inhibitor (CGS 16949A) on the inhibition of tumor growth. Our results show that D2 tumor cells respond well to various aromatase inhibitors and antiestrogens. We examined the usefulness of this model by using D2 tumor cells to simulate postmenopausal breast cancer employing both in vitro cell culture and in vivo ovariectomized (OVX) nude mouse. Unlike DMBA-induced tumors or other models, D2 tumor cells form very rapid tumors within a few days in intact mice or OVX nude mice with androstenedione supplementation and respond well to an aromatase inhibitor. This model with its known mechanism of aromatase activation should be useful for studying the role of intra-tumoral estrogen in mammary cancer, for evaluating the effects of aromatase inhibitors and antiestrogens, and for comparing breast cancer treatments.
Tekmal
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Department of Gynecology and Obstetrics and Winship Cancer Center, Emory University School of Medicine, Atlanta, GA 30322-4710, USA. rtekmal@emory.edu
Durgam
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D015127:9,10-Dimethyl-1,2-benzanthracene; D000616:Aminoglutethimide / Q000633:toxicity; D000704:Analysis of Variance; D000077384:Anastrozole; D000735:Androstenedione / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use / Q000633:toxicity; D001141:Aromatase / Q000096:biosynthesis; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D017316:Fadrozole / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000633:toxicity; D010052:Ovariectomy; D017698:Postmenopause; D014230:Triazoles / Q000633:toxicity; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D000616:Aminoglutethimide; C060523:vorozole; D000077384:Anastrozole; D000735:Androstenedione; D015127:9,10-Dimethyl-1,2-benzanthracene; D001141:Aromatase; D017316:Fadrozole; C080901:leflutrozole