Anti-oestrogen stimulation of ERBB2 ectodomain shedding from BT-474 human breast cancer cells with ERBB2 gene amplification

Oestrogen has previously been shown to downregulate the expression of ERBB2 oncogene in human breast cancer cells, which contain a normal non-amplified ERBB2 gene. However, amplified ERBB2 seems to escape from hormonal regulation. We studied shedding of the extracellular domain (ectodomain, ECD) of...

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Bibliographic Details
Published in:	European journal of cancer (1990) Vol. 32; no. 1; pp. 134 - 140
Main Authors:	Wärri, A.M., Isola, J.J., Härkönen, P.l.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 1996
Subjects:	antioestrogen Blotting, Northern breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism BT-474 cells Cell Division - drug effects Culture Media, Conditioned ectodomain shedding ERBB2 ERBB2 ectodomain ERBB2 gene amplification Estrogen Antagonists - pharmacology Extracellular Space - metabolism Female Gene Expression - drug effects Humans Immunoblotting Receptor, ErbB-2 - drug effects Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism RNA, Messenger - genetics RNA, Neoplasm - genetics toremifene Toremifene - pharmacology Tumor Cells, Cultured ERBB2 gene amplification ectodomain shedding toremifene ERBB2 breast cancer antioestrogen BT-474 cells ERBB2 ectodomain
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Summary:	Oestrogen has previously been shown to downregulate the expression of ERBB2 oncogene in human breast cancer cells, which contain a normal non-amplified ERBB2 gene. However, amplified ERBB2 seems to escape from hormonal regulation. We studied shedding of the extracellular domain (ectodomain, ECD) of the ERBB2 encoded protein in BT-474 human breast cancer cells treated with oestrogen or anti-oestrogen. Oestrogen-responsiveness of these cells has been previously demonstrated by stimulation of cell growth and expression of pS2, a marker gene known to be regulated by oestrogen receptor at transcriptional level. The concentration of the soluble ECD in the culture medium was increased by the anti-oestrogen toremifene as a function of time. In contrast, the level of ERBB2 mRNA and protein in cell lysates was not stimulated, but was transiently suppressed by toremifene. In the presence of oestrogen, the level of ECD remained low. The increased shedding of ECD in the presence of toremifene, without parallel change in ERBB2 transcripts (4.8 and 2.3 kb) and in cellular ERBB2 protein level, suggests that toremifene specifically contributes to the shedding of the ERBB2 ectodomain. These results show that shedding of ECD is an additional level of regulation of ERBB2 by the anti-oestrogen toremifene. This may contribute to resistance to growth inhibition by anti-oestrogens of breast cancers which overexpress ERBB2.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0959-8049 1879-0852
DOI:	10.1016/0959-8049(95)00550-1