Development of antiestrogen resistance is a major clinical problem, and therefore it is crucial to elucidate the mechanisms involved. To investigate whether gain-of-function or loss-of-function mechanisms was most likely to be involved, cell fusion between the antiestrogen-sensitive MCF-7 and the ICI 164384- and ICI 182780-resistant MCF-7/164(R)-5 cell lines was performed. Furthermore, a fusion cell line between the tamoxifen-resistant MCF-7/TAM(R)-1 and the MCF-7/164(R)-5 cell line was established. A thorough investigation of growth parameters and expression of selected proteins (estrogen receptor-alpha (ERalpha), progesterone receptor (PR), Bcl-2, IGF-binding protein-2 (IGFBP2) and IGF receptor Ialpha (IGF-IRalpha)) in the fusion partners and fusion cells revealed that both gain- and loss-of-function changes occurred, and that the mechanisms resulting in resistance to the two antiestrogens were different. This multi-factoriality of antiestrogen resistance is promising in relation to sequential treatment of breast cancer patients with different types of endocrine therapy. Furthermore, we found an association between antiestrogen resistance and reduced IGF-IRalpha expression. Overall, the data presented in this report support the usefulness of cell fusion to clarify the mechanisms involved in development of resistance to the pure antiestrogens ICI 182780 and ICI 164384 and the selective ER modulator tamoxifen and suggest IGF-IRalpha as a new sensitive marker for response to antiestrogen treatment.

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