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Development and characterization of a tamoxifen resistant breast carcinoma xenograft

Item Type:Article
Title:Development and characterization of a tamoxifen resistant breast carcinoma xenograft
Creators Name:Naundorf, H. and Becker, M. and Lykkesfeldt, A.E. and Elbe, B. and Neumann, C. and Buttner, B. and Fichtner, I.
Abstract:A human tamoxifen-resistant mammary carcinoma, MaCa 3366/TAM, originating from a sensitive parental xenograft 3366 was successfully established by treatment of tumour-bearing nude mice with 1-50 mg kg -1 tamoxifen for 3 years during routine passaging. Both tumours did not differ significantly in OR- and PR-positivity, however, when compared with the sensitive tumour line, the mean OR content of the TAM-resistant subline is slightly lower. An OR-upregulation following withdrawal of oestradiol treatment was observed in the parental tumours but not in the resistant xenografts. Following long-term treatment with tamoxifen, the histological pattern of the breast carcinoma changed. The more differentiated structures being apparent after treatment with 17β-oestradiol in the original 3366 tumour were not induced in the resistant line. Tamoxifen failed to induce a tumour growth inhibition in comparison to the tamoxifen-sensitive line. The pure antioestrogen, ICI 182 780, revealed cross-resistance. Sequence analysis of the hormone-binding domain of the OR of both lines showed no differences, suggesting that either mutations in other regions of the OR are involved in the TAM-resistance phenotype or that mechanisms outside of this protein induced this phenotype. Oestrogen and anti-oestrogen regulate pS2 and cathepsin D expression in 3366 tumours as in the human breast cancer cell line MCF-7. The resistant 3366/TAM tumours have lost this regulation. The established breast cancer xenografts 3366 and 3366/TAM offer the possibility of investigating mechanisms of anti-oestrogen resistance in an in vivo situation. They can be used to test novel approaches to prevent, or to overcome, this resistance in a clinically related manner.
Keywords:Breast Cancer, Cathepsin D Gene, Oestrogen Receptor, pS2 Gene, Tamoxifen Resistance, Xenograft, Animals, Mice
Source:British Journal of Cancer
ISSN:0007-0920
Publisher:Nature Publishing Group (U.K.)
Volume:82
Number:11
Page Range:1844-1850
Date:1 June 2000
PubMed:View item in PubMed

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