DIFFERENTIAL EXPRESSION OF ESTROGEN-RECEPTOR MESSENGER-RNA SPLICE VARIANTS IN THE TAMOXIFEN-RESISTANT HUMAN BREAST-CANCER CELL-LINE, MCF-7/TAM(R)-1 COMPARED TO THE PARENTAL MCF-7 CELL-LINE

Breast cancer patients with an estrogen receptor (ER) positive tumor can be treated with the anti-estrogen tamoxifen, but development of anti-estrogen resistance is a serious problem. We have analyzed a tamoxifen resistant human breast cancer cell line MCF-7/TAM(R)-1 for alterations in ER which might explain the tamoxifen resistance. The MCF-7/TAM(R)-1 cells expressed both wild-type ER mRNA and protein, and by RT-PCR we were able to clone ER cDNAs corresponding to the following mRNA splice variants: ER Delta E2, ER Delta E4, ER Delta E5, ER Delta E7 and a new double splice variant lacking both exon 4 and 7 (ER Delta E4,7). The existence of the ER Delta E4,7 variant was confirmed by RNase protection assay. Semi-quantitative RT-PCR revealed that ER Delta E2 mRNA was expressed at a higher level in MCF-7/TAM(R)-1 cells, whereas the ER Delta ES mRNA was expressed at a significantly lower level in MCF-7/TAM(R)-1 cells compared with MCF-7 cells. The differential expression of the two ER mRNA splice variants indicates that they may be involved in anti-estrogen resistance, although the present knowledge of their biological function does not provide us with an explanation.