A critical mechanism that has been proposed for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and that c-Jun chromatin binding shows extensive overlap with ER binding at the global level. Further, we show that c-Jun overexpression reprograms ER chromatin binding and modulates ER-mediated gene regulation. Our data are consistent with a mechanism where estrogen/ER-dependent crosstalk with AP-1 at the transcriptional level is mediated through the tethering of ER to DNA bound AP-1. Additionally, in our system c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated cistrome, transcriptome, and clinical data reveal TGFBI as a candidate gene which may confer tamoxifen resistance by ER and AP-1 crosstalk. Further, we show that TGFBI expression is elevated in breast cancer compared to normal breast. Together, our data provide a novel genome-wide footprint of ER and AP-1 crosstalk and suggest AP-1 and TGFBI signaling as potential therapeutic targets in AP-1-overexpressing ER-positive breast tumors.
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The authors thank the Bioinformatic and Expression Analysis core facility at the Karolinska Institute (http://www.bea.ki.se/) for performing the Affymetrix and ChIP-seq assays and Hui Gao for critically reading the manuscript. This work was supported by scholarship from the China Scholarship Council, a PhD student grant (KID) from the Karolinska Institutet and grants from the Swedish Cancer Society (Cancerfonden).
HH and CZ performed experiments; RF prepared materials; IS and CZ analyzed data; HH, CZ, and KD interpreted results of experiments; HH, CZ, FY, and KD prepared figures; HH and CZ drafted manuscript; HH, L-AH, CZ, and KD edited and revised manuscript; all authors approved final version of manuscript; CZ and KD initiated and designed the study and supervised HH.
Conflict of interest
The authors declare that they have no conflict of interest.
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He, H., Sinha, I., Fan, R. et al. c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer. Oncogene 37, 2586–2600 (2018). https://doi.org/10.1038/s41388-018-0165-8
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