Breast Cancer Research and Treatment

, Volume 131, Issue 3, pp 881–890 | Cite as

FOXA1 is an independent prognostic marker for ER-positive breast cancer

  • Rutika J. Mehta
  • Rohit K. Jain
  • Samuel Leung
  • Jennifer Choo
  • Torsten Nielsen
  • David Huntsman
  • Harikrishna Nakshatri
  • Sunil BadveEmail author
Preclinical Study


Forkhead box protein A1 (FOXA1) is a “pioneer factor” that plays a role in controlling nearly 50% of estrogen receptor target genes. FOXA1 expression correlates with estrogen receptor (ER)-positivity especially in luminal subtype A breast cancers. The aim of this study was to investigate the precise role of FOXA1 in breast cancer using a large population-based cohort. Nuclear expression of FOXA1 was analyzed in a tissue microarray of 4,444 invasive breast cancer cases using immunohistochemistry and correlated with clinicopathologic variables using previously described methods and cutoff points. The entire cohort was equally divided into a training and validation set. All survival analyses were performed using a previously defined cutoff (3) for validation. Additional X-tile analysis performed to analyze prognostic effects of low and high FOXA1 levels identified 24 as a cutoff. Bonferroni–Holmes test was used as appropriate. FOXA1 expression significantly correlated positively with markers of good prognosis or ER-positivity, and negatively with tumor size, tumor grade, nodal status, Ki67, HER2 expression, and basal subtype (each P value <0.0001). In both survival analyses, FOXA1 was a significant predictor of breast cancer-specific survival (P < 0.0001) and relapse-free survival (P < 0.0001). FOXA1 was also an independent predictor of breast cancer-specific survival at 10 years using both cutoffs. Among the ER-positive subgroup treated with tamoxifen, FOXA1 was an independent prognostic marker using the 24 cutoff (P = 0.030). FOXA1 is a significant marker of good prognosis in breast cancer; it also identifies a subset of ER-positive tamoxifen treated patients at low risk of recurrence.


FOXA1 expression ER PR Breast cancer Tissue microarray Prognostic significance 



The Genetic Pathology Evaluation Centre is supported by an unrestricted educational grant from Sanofi-aventis Canada. We thank Caroline Speers and members of the Breast Cancer Outcomes Unit for clinical database management. The authors would also like to thank Dr. Kathy Miller, Indiana University for critical review and comments.

Conflicts of interest

Authors HN and SB have an invention disclosure with Indiana University for the use of FOXA1 as a prognostic marker in breast cancer. Both SB and HN are supported by grants from Susan G Komen Foundation.

Supplementary material

10549_2011_1482_MOESM1_ESM.docx (13 kb)
Supplementary Table 1 Description of the cohort of 4046 breast cancer patients for important clinic-pathological variables. (DOCX 14 kb)
10549_2011_1482_MOESM2_ESM.doc (46 kb)
Supplementary Table 2 Description of univariate survival analyses for important variables in the entire cohort (n = 4046). (DOC 47 kb)
10549_2011_1482_MOESM3_ESM.docx (16 kb)
Supplementary Table 3 Correlation of FOXA1 categories (<3 vs. ≥3) with important clinic-pathological variables in training and validation cohorts. (DOCX 16 kb)
10549_2011_1482_MOESM4_ESM.docx (15 kb)
Supplementary Table 4 Correlation of FOXA1 categories (<3 vs. ≥3) with important clinic-pathological variables in the entire cohort. (DOCX 15 kb)
10549_2011_1482_MOESM5_ESM.docx (16 kb)
Supplementary Table 5 Description of survival analyses comparing low versus high FOXA1 expression in 4,046 breast cancer cases with longer follow-up. This table has two parts; top portion displaying results of univariate analyses and the bottom portion displaying the various models used for multivariate analysis. All results have been shown for both Parts A and B of the survival analyses with a longer followup. (DOCX 16 kb)
10549_2011_1482_MOESM6_ESM.xlsx (12 kb)
Supplementary Table 6 Table showing P-values after Bonferroni–Holmes correction for associations of FOXA1 expression with different clinicopathologic variables in training, validation, and entire cohort. *All survival analyses have been shown primarily for 10 years time period unless stated otherwise. (XLSX 12 kb)
10549_2011_1482_MOESM7_ESM.pptx (38 kb)
Supplementary Figure 1 Schematic representation of the study design; (A) shows how the 3 cutoff was used in this study that was initially derived from our previous work and (B) shows how the 24 cutoff was derived from a separate X-tile analysis of this cohort. (PPTX 39 kb)
10549_2011_1482_MOESM8_ESM.pptx (725 kb)
Supplementary Figure 2 Representative staining of FOXA1 in breast cancer using immunohistochemistry; A- no expression vs. B- strong expression (PPTX 726 kb)
10549_2011_1482_MOESM9_ESM.pptx (272 kb)
Supplementary Figure 3 Kaplan–Meier curve demonstrating impact of FOXA1 expression on BCSS and RFS at 20 years. The top panel displays the survival functions using a 3 cutoff while the same with a 24 cutoff has been shown in the bottom panel. The curves clearly show that cases with high FOXA1 expression (either >3 or >24) have a better prognosis than those with low expression. This identifies the prognostic impact of FOXA1 in breast cancer. (PPTX 272 kb)
10549_2011_1482_MOESM10_ESM.pptx (129 kb)
Supplementary Figure 4 Kaplan–Meier curves demonstrating impact of FOXA1 expression on survival among ER-positive cases not receiving any systemic therapy. This identifies the ability of FOXA1 to be an important marker among ER-positive cases that have good prognosis even in the absence of any systemic therapy. High FOXA1 expression (either >3 or >24) has better prognosis than low expression in this subgroup. (PPTX 129 kb)
10549_2011_1482_MOESM11_ESM.pptx (142 kb)
Supplementary Figure 5 Kaplan–Meier curves demonstrating impact of FOXA1 in all ER-positive patients. These curves show that high FOXA1 expression (either >3 or >24) have better prognosis than those with low expression in ER-positive patients. No treatment subgroups have been considered for this particular analysis. (PPTX 142 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Rutika J. Mehta
    • 2
  • Rohit K. Jain
    • 2
  • Samuel Leung
    • 4
  • Jennifer Choo
    • 4
  • Torsten Nielsen
    • 4
  • David Huntsman
    • 4
  • Harikrishna Nakshatri
    • 5
  • Sunil Badve
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of MedicineIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  3. 3.Indiana University Melvin and Bren Simon Cancer CenterIndianapolisUSA
  4. 4.Genetic Pathology Evaluation CenterUniversity of British ColumbiaVancouverCanada
  5. 5.Department of SurgeryIndiana University School of MedicineIndianapolisUSA

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