Decreased COUP‐TFII expression in tamoxifen resistant breast cancer

Abstract

Tamoxifen (TAM) has been widely used successfully for the treatment and prevention of breast cancer. Many initially TAM-responsive tumors develop TAM-resistance. The mechanism behind TAM-resistance in estrogen receptor α (ERα-positive tumors is not yet understood. The orphan nuclear receptors chicken ovalbumin upstream promoter transcription factors (COUP-TFI and COUP-TFII) interact directly with 4-hydroxytamoxifen (4-OHT)- and estradiol (E2)- occupied ERα, corepressors NCoR and SMRT, and inhibit E2-activated ERα transcription in breast cancer cells. COUP-TFII expression is reduced in some breast tumors. Here we tested the hypothesis that reduced expression of COUP-TFI and COUP-TFII plays a role in TAM resistance. The expression of COUP-TFI and -TFII was examined in TAM-sensitive (TAM-S) MCF-7 human breast cancer cells and sublines of MCF-7 that are TAM-resistant (TAM-R) as well as the ERα-negative MDA-MB-231. We found no difference in ERα or ER β protein expression between TAM-S versus TAM-R cell lines, but TAM-R cells showed decreased progesterone receptor (PR) expression. Importantly, COUP-TFII, but not COUP-TFI, expression was reduced in TAM-R cell lines and re-expression of COUP-TFII increased 4-OHT inhibition. Knockdown of COUP-TFII expression in TAM-S cells decreased 4-OHT's inhibition of cell proliferation and increased its ER agonist activity. These data indicate that reduced COUP-TFII expression may play a role in regulating the expression of genes involved in TAM-resistance and may provide another biomarker for predicting patient prognosis. Supported by a NIEHS T32 ES011564 training grant pre-doctoral fellowship to K.A.R. and grant BCTR0201438 from the Susan G. Komen Breast Cancer Foundation to C.M.K.