Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family

Development of acquired resistance against antiestrogen treatment is a seri ous problem in human breast cancer, and knowledge of alterations resulting in resistance is important for selection of further treatment. To mimic the clinical situation we have established a series of MCF-7 human breast canc er cell lines by long term treatment with the antiestrogens tamoxifen, ICI 164,384, and ICI 182,780. Common for these cell lines is a decreased expres sion of the estrogen receptor alpha (ER alpha). In human breast cancer, lac k of response to endocrine therapy is often associated with decreased expre ssion of the estrogen receptor and increased expression of epidermal growth factor receptor (EGFR) and/or HER-2/neu (ErbB-2). Our antiestrogen resista nt cell lines did not express altered levels of EGFR, HER-2/neu, ErbB-3, or ErbB-4. Estrogen and antiestrogen regulation of HER-2/neu expression was e ssentially similar in parent and resistant MCF-7 cells. Treatment with anti bodies to HER-2/neu (Herceptin(TM)) did not affect growth of MCF-7 cells or resistant cells, indicating that in this in vitro model system, acquired a ntiestrogen resistance does not emerge from activation of the HER-2/neu sig naling pathway. In MCF-7 cells transfected with HER-2/neu and/or ErbB-3, ov erexpression alone did not result in resistance. However, addition of hereg ulinl-beta 1 abolished the inhibitory activity of ICI 182,780 on both vecto r and HER-2/neu/ErbB-3 transfected MCF-7 cells, demonstrating that activati on of the HER-2/neu receptor signaling pathway can override the growth inhi bitory effect of ICI 182,780.