Skip to main content
  • Viewpoint
  • Published:

A functional link between FOXA1 and breast cancer SNPs


Genome-wide association studies have revealed a multitude of breast cancer-associated SNPs. The majority of these SNPs are located in noncoding regions of the genome. Yet how they contribute to breast cancer development is unknown. Recently, a groundbreaking study by the Lupien group has shown that risk-associated SNPs of breast cancer are enriched for FOXA1 binding sites, which influences the function of this transcription factor.


Breast cancer is a heterogeneous disease and the most frequent tumors are positive for the expression of estrogen receptor (ER) [1] or the epidermal growth factor receptor 2 (HER2) [2]. The transcription factor FOXA1 is a common feature for the majority of these tumors [3, 4]. Genomic analyses have revealed that the binding of FOXA1 shows a tissue-specific occupancy and that it is associated with the binding of ER or androgen receptor [58]. FOXA1 recruitment to chromatin is mediated by the epigenetic signature consisting of monomethylated and dimethylated histone H3 on lysine 4 (H3K4me1,2) [6].

In the last years, genomic studies have uncovered a multitude of SNPs associated with the risk of breast cancer. However, given that these SNPs are often found in non-coding regions [9], it was unclear how they could be contributing to the development of the disease [10].


In a seminal study published in Nature Genetics, Cowper-Sal Lari and colleagues have integrated genomic methodologies to identify the functional relationship between risk-associated SNPs with high linkage disequilibrium and the transcription factor binding or histone modifications in ER-positive breast cancer subtype [11]. To check the enrichment of risk-associated SNPs in chromatin regions, the authors employed variant-set enrichment analysis. Using this statistical analysis tool, they identified that the breast cancer-associated variant set is strongly enriched for FOXA1, ER binding regions and histone modification H3K4me1 marks. Importantly, the associated variant set from other diseases (for example, prostate cancer, colorectal cancer and bone cancer) did not show the same correlation. Based on these findings, the authors state that the enrichment of the breast cancer-associated SNPs for these transcription factors and histone mark are both cancer type specific and tissue specific.

Having shown that breast cancer risk-associated SNPs are enriched with FOXA1 binding sites, the authors tested how these SNPs modulate the binding of the transcription factor to chromatin. They used the intragenomic replicates method, which establishes the effect of individual SNPs on the affinity of a transcription factor binding to chromatin. The authors focused on one of the most studied risk-associated SNPs: rs4784227, which maps within the forkhead motif for FOXA1 genomic interaction. Interestingly, FOXA1 binding affinity was increased for the [T] variant allele compared with the [C] reference allele. Extensive intragenomic replicates analysis and variant-set enrichment analysis on all SNP clusters indicated that more than one-half of them are associated with altered affinity of FOXA1 to chromatin.

To verify the effect of the SNP on breast cancer progression the authors focused on the TOX3 gene, which is localized in the rs4784227 risk-associated region. They used chromatin conformation capture assays and they confirmed a physical interaction between the rs4784227 region and the promoter of the TOX3 gene. This result confirms that TOX3 is a gene target of the regulatory region harboring the SNP. Furthermore, the authors analyzed the impact of the different alleles on TOX3 gene expression performing allele-specific expression assay. With this method they showed that the [T] variant allele has a repressive effect on TOX3 expression. Finally, the depletion of TOX3 gene increased significantly the proliferation of breast cancer cells.


The published study opens a new way to understand the impact of risk-associated SNPs on breast cancer disease. Importantly, the authors have identified a subset of FOXA1 binding regions enriched for risk-associated SNPs, which immediately raises the question of whether the remaining FOXA1 regions also play a critical role in the progression of the disease. On the contrary, not all breast cancer-associated SNPs were associated with FOXA1 binding regions. In future studies it will therefore be of interest to investigate the effect of these SNPs on other transcription factors.

Furthermore, the study concludes that more than one-half of the risk-associated SNPs influence FOXA1 binding [11]. FOXA1 has been described to function as a pioneer factor that allows the binding of ER and Androgen Receptor [5]. Recently, the expression of FOXA1 both in ER and HER2 breast cancer cell lines has been also reported to repress transcription [12]. Whether the SNPs are influencing both or any of these functions needs to be determined.

Finally, the study also reports that the depletion of TOX3 increased significantly the proliferation of breast cancer cells, suggesting that the rs4784227 risk-associated region might be used as a clinical marker for cancer prognosis. Investigating how other SNPs could impact current breast cancer treatments will be important. The use of SNPs as biomarkers to predict anticancer drug efficacy and risk levels in breast cancer patients is a promising path to explore.



estrogen receptor


epidermal growth factor receptor 2


single nucleotide polymorphism.


  1. Dowsett M: Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer. Endocr Relat Cancer. 2001, 8: 191-195. 10.1677/erc.0.0080191.

    Article  CAS  PubMed  Google Scholar 

  2. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007, 25: 118-145.

    Article  CAS  PubMed  Google Scholar 

  3. Hisamatsu Y, Tokunaga E, Yamashita N, Akiyoshi S, Okada S, Nakashima Y, Aishima S, Morita M, Kakeji Y, Maehara Y: Impact of FOXA1 expression on the prognosis of patients with hormone receptor-positive breast cancer. Ann Surg Oncol. 2012, 19: 1145-1152. 10.1245/s10434-011-2094-4.

    Article  PubMed  Google Scholar 

  4. Yamaguchi N, Ito E, Azuma S, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Tatsuta K, Inoue J, Semba K, Watanabe S: FoxA1 as a lineage-specific oncogene in luminal type breast cancer. Biochem Biophys Res Commun. 2008, 365: 711-717. 10.1016/j.bbrc.2007.11.064.

    Article  CAS  PubMed  Google Scholar 

  5. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS: FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet. 2011, 43: 27-33. 10.1038/ng.730.

    Article  CAS  PubMed  Google Scholar 

  6. Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M: FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell. 2008, 132: 958-970. 10.1016/j.cell.2008.01.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Serandour AA, Avner S, Percevault F, Demay F, Bizot M, Lucchetti-Miganeh C, Barloy-Hubler F, Brown M, Lupien M, Metivier R, Salbert G, Eeckhoute J: Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res. 2011, 21: 555-565. 10.1101/gr.111534.110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG, Carroll JS: Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011, 30: 3019-3027. 10.1038/emboj.2012.59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Frazer KA, Murray SS, Schork NJ, Topol EJ: Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009, 10: 241-251.

    Article  CAS  PubMed  Google Scholar 

  10. Genomes Project C: A map of human genome variation from populationscale sequencing. Nature. 2010, 467: 1061-1073. 10.1038/nature09534.

    Article  Google Scholar 

  11. Cowper-Sal Lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, Lupien M: Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet. 2012, 44: 1191-1198. 10.1038/ng.2416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bernardo GM, Bebek G, Ginther CL, Sizemore ST, Lozada KL, Miedler JD, Anderson LA, Godwin AK, Abdul-Karim FW, Slamon DJ, Keri R: FOXA1 represses the molecular phenotype of basal breast cancer cells. Oncogene. 2013, 32: 554-563. 10.1038/onc.2012.62.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Antoni Hurtado.

Additional information

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katika, M.R., Hurtado, A. A functional link between FOXA1 and breast cancer SNPs. Breast Cancer Res 15, 303 (2013).

Download citation

  • Published:

  • DOI: