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FOXA1 is a key determinant of estrogen receptor function and endocrine response

Nature Genetics volume 43, pages 27–33 (2011)Cite this article

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Abstract

Estrogen receptor-α (ER) is the key feature of most breast cancers and binding of ER to the genome correlates with expression of the Forkhead protein FOXA1 (also called HNF3α). Here we show that FOXA1 is a key determinant that can influence differential interactions between ER and chromatin. Almost all ER-chromatin interactions and gene expression changes depended on the presence of FOXA1 and FOXA1 influenced genome-wide chromatin accessibility. Furthermore, we found that CTCF was an upstream negative regulator of FOXA1-chromatin interactions. In estrogen-responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity was absolute; in tamoxifen-resistant cells, ER binding was independent of ligand but depended on FOXA1. Expression of FOXA1 in non-breast cancer cells can alter ER binding and function. As such, FOXA1 is a major determinant of estrogen-ER activity and endocrine response in breast cancer cells.

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Figure 1: Differential binding of FOXA1 and ER overlaps in a cell context–dependent manner.
Figure 2: Binding of ER to chromatin and transcriptional activity requires FOXA1.
Figure 3: Tamoxifen induces similar ER binding events to estrogen in a FOXA1-dependent manner.
Figure 4: FOXA1 expression in U20S-ER osteosarcoma cancer cells renders ER functional.
Figure 5: FOXA1 is required for maintaining chromatin structure.
Figure 6: Binding events that are shared between ER and FOXA1 are exclusively independent of CTCF, and CTCF can repress the binding and activity of FOXA1.

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Acknowledgements

We thank G. Brown, R. Russell and R. Stark for bioinformatics support; J. Hadfield for genomic help; S. Vowler for statistical advice; and T. Spelsberg and I. Hutcheson for cell lines. We acknowledge support from The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. C.S.R.-I. is supported by a Commonwealth fellowship, K.A.H. is supported by a Breast Cancer Campaign grant and J.S.C. and A.H. are supported by an ERC Starting Grant.

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  1. Antoni Hurtado and Kelly A Holmes: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

    Antoni Hurtado, Kelly A Holmes, Caryn S Ross-Innes, Dominic Schmidt & Jason S Carroll

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  1. Antoni Hurtado
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Contributions

All experiments were conceived by A.H., K.A.H. and J.S.C. Experiments were conducted by A.H., K.A.H. and C.S.R.-I. Computational analysis was conducted by A.H. and D.S. The manuscript was written by A.H., K.A.H. and J.S.C. with help from C.S.R.-I. and D.S.

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Correspondence to Jason S Carroll.

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Hurtado, A., Holmes, K., Ross-Innes, C. et al. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 43, 27–33 (2011). https://doi.org/10.1038/ng.730

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