Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor β and AP-1 recruitment to adjacent promoter binding sites

Little is known about endogenous estrogen receptor beta (ER beta) gene targets in human breast cancer. We reported that estradiol (E-2) induces nuclear respiratory factor-1 (NRF-1) transcription through ER alpha in MCF-7 breast cancer cells. Here we report that 4-hydroxytamoxifen (4-OHT), with an EC50 of similar to 1.7 nM, increases NRF-1 expression by recruiting ER beta, cJun, cFos, CBP, and RNA polymerase II to and dismissing NCoR from the NRF1 promoter. Promoter deletion and transient transfection studies showed that the estrogen response element (ERE) is essential and that an adjacent AP-1 site contributes to maximal 4-OHT-induced NRF-1 transcription. siRNA knockdown of ER beta revealed that ER beta inhibits basal NRF-1 expression and is required for 4-OHT-induced NRF-1 transcription. An AP-1 inhibitor blocked 4-OHT-induced NRF-1 expression. The 4-OHT-induced increase in NRF-1 resulted in increased transcription of NRF-1 target CAPNS1 but not CYC1, CYC2, or TFAM despite increased NRF-1 coactivator PGC-1 alpha protein. The absence of TFAM induction corresponds to a lack of Akt-dependent phosphorylation of NRF-1 with 4-OHT treatment. Overexpression of NRF-1 inhibited 4-OHT-induced apoptosis and siRNA knockdown of NRF-1 increased apoptosis, indicating an antiapoptotic role for NRF-1. Overall, NRF-1 expression and activity is regulated by 4-OHT via endogenous ER beta in MCF-7 cells.-Ivanova, M. M., Luken, K. H., Zimmer, A. S., Lenzo, F. L., Smith, R. J., Arteel, M. W., Kollenberg, T. J., Mattingly, K. A., Klinge, C. M. Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor beta and AP-1 recruitment to adjacent promoter binding sites. FASEB J. 25, 1402-1416 (2011). www.fasebj.org