Abstract
Tamoxifen (TAM) is successfully used for the treatment and prevention of breast cancer. However, many patients that are initially TAM responsive develop tumors that are antiestrogen/TAM resistant (TAM-R). The mechanism behind TAM resistance in estrogen receptor alpha (ERalpha)-positive tumors is not understood. The orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF)-I interacts directly with 4-hydroxytamoxifen (4-OHT)- and estradiol (E(2))-occupied ERalpha, corepressors NCoR and SMRT, and inhibit E(2)-induced gene transcription in breast cancer cells. Here we tested the hypothesis that reduced COUP-TFI and COUP-TFII correlate with TAM resistance. We report for the first time that COUP-TFII, but not COUP-TFI, is reduced in three antiestrogen/TAM-R cell lines derived from TAM-sensitive (TAM-S) MCF-7 human breast cancer cells and in MDA-MB-231 cells compared with MCF-7. ERalpha and ERbeta protein expression was not different between TAM-S and TAM-R cells, but progesterone receptor (PR) was decreased in TAM-R cells. Further, E(2) increased COUP-TFII transcription in MCF-7, but not TAM-R, cells. Importantly, reexpression of COUP-TFII in TAM-S cells to levels comparable to those in MCF-7 was shown to increase 4-OHT-mediated growth inhibition and increased apoptosis. Conversely, knockdown of COUP-TFII in TAM-S MCF-7 cells blocked growth inhibitory activity and increased 4-OHT agonist activity. 4-OHT increased COUP-TFII-ERalpha interaction approximately 2-fold in MCF-7 cells. COUP-TFII expression in TAM-R cells also inhibited 4-OHT-induced endogenous PR and pS2 mRNA expression. These data indicate that reduced COUP-TFII expression correlates with acquired TAM resistance in human breast cancer cell lines and that COUP-TFII plays a role in regulating the growth inhibitory activity of TAM in breast cancer cells.
Highlights
Breast cancer is the second leading cause of cancer deaths in women in the United States, surpassed only by lung cancer [1]
Because MCF-7 breast cancer cell lines are notorious for changes in phenotype between labs [32], the reported phenotypic growth responses of the cell lines were first evaluated by examining cell proliferation in response to E2, 4-OHT, and ICI 182,780, alone or in combination, using MTT assays (Supplementary Fig. S1)
COUP-TFII expression was increased by f2, 4, and 1.7-fold in the stably transfected LY2, LCC2, and LCC9 cell lines (Fig. 3A); COUP-TFII was similar to endogenous COUP-TFII expression in MCF-7 cells in the LY2-CII and LCC9-CII cell lines
Summary
Breast cancer is the second leading cause of cancer deaths in women in the United States, surpassed only by lung cancer [1]. (TAM) is a widely used endocrine therapy for the prevention and treatment of estrogen receptor (ER)–positive breast cancer [2]. TAM and its active metabolite, 4-hydroxytamoxifen (4-OHT), are antiestrogens that inhibit tumor cell proliferation by competing with estrogens for ER and thereby inhibiting transcription of estrogen target genes [2]. In addition to being effective against existing tumors, TAM is used as a breast cancer preventative treatment in high-risk patients [2, 3]. Expression of ERa is used as a clinical marker to predict patient response to treatment and survival [4]. 35% to 50% of ERa-positive breast tumors that initially respond to TAM develop acquired TAM resistance, no longer responding to the growth inhibitory effect of TAM [2]. TAM resistance is a significant clinical problem resulting in the requirement for alternative therapies. Antiestrogen resistance results from a loss of ERa expression [5], but in many TAM-resistant (TAM-R) tumors, ERa is still expressed [2]
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