Skip to main content

Advertisement

SpringerLink
Log in

Time-varying effects of FOXA1 on breast cancer prognosis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Results of previous studies on the associations between Forkhead box A1 (FOXA1) expression in breast cancer tissues and the prognosis varied depending on the follow-up durations. The present study would investigate whether there is a time-varying effect of FOXA1 in breast cancer tissues on the prognosis.

Methods

FOXA1 expressions were evaluated in 1041 primary invasive breast tumors with tissue microarrays by immunohistochemistry. Cox models with restricted cubic splines and Kaplan–Meier survival analysis were used to examine the associations between FOXA1 and the prognosis. Flexible parametric models were applied to explore the time-varying effect of FOXA1.

Results

Overall, the association between FOXA1 expression and the prognosis was not significant but varied on the time of follow-up. Compared to FOXA1 ≤ 270 of H-score, the hazard ratios (HRs) of death for those with 271–285 of FOXA1 expression increased from 0.35 (95% CI 0.14–0.86) at 6 months after diagnosis to 2.88 (95% CI 1.35–6.15) at 120 months with a crossover at around 36 months. Similar patterns were also observed for FOXA1 > 285 of H-score and for progression free survival (PFS). Moreover, when allowed both FOXA1 and estrogen receptor (ER) to change over time in the model (considering that ER had a similar time-varying effect), these time-varying effects remained for FOXA1 on both overall survival (OS) (P < 0.01) and PFS (P = 0.01) but were attenuated for ER (P = 0.13 for OS).

Conclusions

This study revealed an independent time-varying effect of FOXA1 on breast cancer prognosis, which would provide an insight into the roles of FOXA1 as a marker of breast cancer prognosis and may help optimize the medication strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

DAB:

Diaminobenzidine

ER:

Estrogen receptor

EMT:

Epithelial to mesenchymal transition

FOXA1:

Forkhead box A1

HE:

Hematoxylin and eosin

HER-2:

Human epidermal growth factor receptor 2

HR:

Hazard ratio

IHC:

Immunohistochemistry

Ki-67:

Proliferation index factor Ki-67

OS:

Overall survival

PFS:

Progression free survival

PR:

Progesterone receptor

TMA:

Tissue microarray

References

  1. Augello MA, Hickey TE, Knudsen KE (2011) FOXA1: master of steroid receptor function in cancer. Embo J 30:3885–3894. https://doi.org/10.1038/emboj.2011.340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bernardo GM, Keri RA (2012) FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep 32:113–130. https://doi.org/10.1042/bsr20110046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zheng L, Qian B, Tian D, Tang T, Wan S, Wang L, Zhu L, Geng X (2015) FOXA1 positively regulates gene expression by changing gene methylation status in human breast cancer MCF-7 cells. Int J Clin Exp Pathol 8:96–106

    PubMed  PubMed Central  Google Scholar 

  4. Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH (2005) Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24:8277–8290. https://doi.org/10.1038/sj.onc.1208991

    Article  CAS  PubMed  Google Scholar 

  5. Williamson EA, Wolf I, O’Kelly J, Bose S, Tanosaki S, Koeffler HP (2006) BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1). Oncogene 25:1391–1399. https://doi.org/10.1038/sj.onc.1209170

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Robinson JL, Carroll JS (2012) FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front Endocrinol (Lausanne) 3:68. https://doi.org/10.3389/fendo.2012.00068

    Article  CAS  Google Scholar 

  8. Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, Brown GD, Gojis O, Ellis IO, Green AR, Ali S, Chin SF, Palmieri C, Caldas C, Carroll JS (2012) Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481:389–393. https://doi.org/10.1038/nature10730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Rangel N, Fortunati N, Osella-Abate S, Annaratone L, Isella C, Catalano MG, Rinella L, Metovic J, Boldorini R, Balmativola D, Ferrando P, Marano F, Cassoni P, Sapino A, Castellano I (2018) FOXA1 and AR in invasive breast cancer: new findings on their co-expression and impact on prognosis in ER-positive patients. BMC Cancer 18:703. https://doi.org/10.1186/s12885-018-4624-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, Costa S, Vieira D, Lopes N, Lam EW, Lunet N, Schmitt F (2009) Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours. Breast Cancer Res 11:R40. https://doi.org/10.1186/bcr2327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jiang G, Wang X, Sheng D, Zhou L, Liu Y, Xu C, Liu S, Zhang J (2019) Cooperativity of co-factor NR2F2 with pioneer factors GATA3, FOXA1 in promoting ERα function. Theranostics 9:6501–6516. https://doi.org/10.7150/thno.34874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang YW, Ma J, Shi CT, Han W, Gao XJ, Zhou MH, Ding HZ, Wang HN (2020) Roles and correlation of FOXA1 and ZIC1 in breast cancer. Curr Probl Cancer. https://doi.org/10.1016/j.currproblcancer.2020.100559

    Article  PubMed  Google Scholar 

  14. Fu X, Jeselsohn R, Pereira R, Hollingsworth EF, Creighton CJ, Li F, Shea M, Nardone A, De Angelis C, Heiser LM, Anur P, Wang N, Grasso CS, Spellman PT, Griffith OL, Tsimelzon A, Gutierrez C, Huang S, Edwards DP, Trivedi MV, Rimawi MF, Lopez-Terrada D, Hilsenbeck SG, Gray JW, Brown M, Osborne CK, Schiff R (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci USA 113:E6600–E6609. https://doi.org/10.1073/pnas.1612835113

    Article  CAS  PubMed  Google Scholar 

  15. Habashy HO, Powe DG, Rakha EA, Ball G, Paish C, Gee J, Nicholson RI, Ellis IO (2008) Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance. Eur J Cancer 44:1541–1551. https://doi.org/10.1016/j.ejca.2008.04.020

    Article  CAS  PubMed  Google Scholar 

  16. Mehta RJ, Jain RK, Leung S, Choo J, Nielsen T, Huntsman D, Nakshatri H, Badve S (2012) FOXA1 is an independent prognostic marker for ER-positive breast cancer. Breast Cancer Res Treat 131:881–890. https://doi.org/10.1007/s10549-011-1482-6

    Article  CAS  PubMed  Google Scholar 

  17. Horimoto Y, Sasahara N, Sasaki R, Hlaing MT, Sakaguchi A, Saeki H, Arakawa A, Himuro T, Saito M (2020) High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer. Breast Cancer Res Treat 183:41–48. https://doi.org/10.1007/s10549-020-05751-x

    Article  CAS  PubMed  Google Scholar 

  18. He JR, Tang LY, Yu DD, Su FX, Song EW, Lin Y, Wang SM, Lai GC, Chen WQ, Ren ZF (2011) Epstein-Barr virus and breast cancer: serological study in a high-incidence area of nasopharyngeal carcinoma. Cancer Lett 309:128–136. https://doi.org/10.1016/j.canlet.2011.05.012

    Article  CAS  PubMed  Google Scholar 

  19. He K, Zeng H, Xu X, Li A, Cai Q, Long X (2016) Clinicopathological significance of forkhead box protein A1 in breast cancer: a meta-analysis. Exp Ther Med 11:2525–2530. https://doi.org/10.3892/etm.2016.3229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheng TD, Yao S, Omilian AR, Khoury T, Buas MF, Payne-Ondracek R, Sribenja S, Bshara W, Hong CC, Bandera EV, Davis W, Higgins MJ, Ambrosone CB (2020) foxa1 protein expression in ER(+) and ER(-) breast cancer in relation to parity and breastfeeding in black and white women. Cancer Epidemiol Biomark Prev 29:379–385. https://doi.org/10.1158/1055-9965.Epi-19-0787

    Article  CAS  Google Scholar 

  21. Xu Y, Qin L, Sun T, Wu H, He T, Yang Z, Mo Q, Liao L, Xu J (2017) Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene 36:1157–1166. https://doi.org/10.1038/onc.2016.286

    Article  CAS  PubMed  Google Scholar 

  22. Zhang XL, Wang HS, Liu N, Ge LC (2015) Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals. Arch Biochem Biophys 585:10–16. https://doi.org/10.1016/j.abb.2015.09.006

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi N, Nakayama Y, Yamaguchi N (2017) Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6. J Biol Chem 292:8136–8148. https://doi.org/10.1074/jbc.M116.763276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chinese Anti-Cancer Association Committee of Breast Cancer Society (2008) Chinese Anti-Cancer Association (CSCA) diagnosis and treatment guidelines for breast cancer (version 2008). Chin Oncol 19:448–474. https://doi.org/10.3969/j.issn.1007-3639.2009.06.012

    Article  Google Scholar 

  25. Xu H, Jin F, Zhang XJ, Wang DQ, Yu SF, Wang AP (2020) Adherence status to adjuvant endocrine therapy in Chinese Women with Early Breast Cancer and its influencing factors: a cross-sectional survey. Cancer Med 9:3703–3713. https://doi.org/10.1002/cam4.3017

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fu X, Pereira R, De Angelis C, Veeraraghavan J, Nanda S, Qin L, Cataldo ML, Sethunath V, Mehravaran S, Gutierrez C, Chamness GC, Feng Q, O’Malley BW, Selenica P, Weigelt B, Reis-Filho JS, Cohen O, Wagle N, Nardone A, Jeselsohn R, Brown M, Rimawi MF, Osborne CK, Schiff R (2019) FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer. Proc Natl Acad Sci USA 116:26823–26834. https://doi.org/10.1073/pnas.1911584116

    Article  CAS  Google Scholar 

  27. Tokunaga E, Hisamatsu Y, Tanaka K, Yamashita N, Saeki H, Oki E, Kitao H, Maehara Y (2014) Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Sci 105:1377–1383. https://doi.org/10.1111/cas.12521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Piggin CL, Roden DL, Law AMK, Molloy MP, Krisp C, Swarbrick A, Naylor MJ, Kalyuga M, Kaplan W, Oakes SR, Gallego-Ortega D, Clark SJ, Carroll JS, Bartonicek N, Ormandy CJ (2020) ELF5 modulates the estrogen receptor cistrome in breast cancer. PLoS Genet 16:e1008531. https://doi.org/10.1371/journal.pgen.1008531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bernardo GM, Lozada KL, Miedler JD, Harburg G, Hewitt SC, Mosley JD, Godwin AK, Korach KS, Visvader JE, Kaestner KH, Abdul-Karim FW, Montano MM, Keri RA (2010) FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis. Development 137:2045–2054. https://doi.org/10.1242/dev.043299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, Fox EA, Silver PA, Brown M (2005) Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122:33–43. https://doi.org/10.1016/j.cell.2005.05.008

    Article  CAS  PubMed  Google Scholar 

  31. Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG, Carroll JS (2011) Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. Embo J 30:3019–3027. https://doi.org/10.1038/emboj.2011.216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cocce KJ, Jasper JS, Desautels TK, Everett L, Wardell S, Westerling T, Baldi R, Wright TM, Tavares K, Yllanes A, Bae Y, Blitzer JT, Logsdon C, Rakiec DP, Ruddy DA, Jiang T, Broadwater G, Hyslop T, Hall A, Laine M, Phung L, Greene GL, Martin LA, Pancholi S, Dowsett M, Detre S, Marks JR, Crawford GE, Brown M, Norris JD, Chang CY, McDonnell DP (2019) The lineage determining factor GRHL2 collaborates with FOXA1 to establish a targetable pathway in endocrine therapy-resistant breast cancer. Cell Rep 29:889-903.e810. https://doi.org/10.1016/j.celrep.2019.09.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wright TM, Wardell SE, Jasper JS, Stice JP, Safi R, Nelson ER, McDonnell DP (2014) Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Mol Cancer Res 12:1829–1839. https://doi.org/10.1158/1541-7786.Mcr-14-0195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sincerely thank the patients who participated in this study, the staff who conducted the baseline and the follow‐up data collection, and the medical staff in the breast departments of the First Affiliated Hospital, and the Cancer Center of Sun Yat‐Sen University.

Funding

This research was funded by National Natural Science Foundation of China (81773515 and 81973115) and Science and Technology Planning Project of Guangdong Province, China (2019B030316002). The founders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Qian-xin Chen and Yuan-zhong Yang have contributed equally to this work.

Authors and Affiliations

  1. School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, China

    Qian-xin Chen, Zhuo-zhi Liang, Jia-li Chen, Yue-lin Li, Zi-yi Huang & Ze-fang Ren

  2. The Sun Yat-Sen University Cancer Center, Guangzhou, 510080, China

    Yuan-zhong Yang & Jing-ping Yun

  3. Guangzhou Institute of Dermatology, Guangzhou, 510095, China

    Jia-li Chen

  4. The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Yue-lin Li

  5. The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Zi-jin Weng, Xiao-fang Zhang, Jie-xia Guan & Lu-ying Tang

Authors
  1. Qian-xin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan-zhong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuo-zhi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia-li Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yue-lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zi-yi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zi-jin Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao-fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie-xia Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lu-ying Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jing-ping Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ze-fang Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QC, ZR, and JY designed and directed the study, wrote and/or revise the manuscript. YY and YL constructed the TMAs. YY contributed to the IHC. ZW, XZ, JG, and LT contributed to digital imaging of IHC-stained sections and the assessment of immunohistochemical expression. QC, ZL, ZH, JC and YL contributed to clinical data collection and curation. QC, ZL, and ZH participated in the statistical analysis plan and interpretation of results. ZR, and JY provided administrative support and supervision for the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jing-ping Yun or Ze-fang Ren.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The study was approved by the ethics committee of School of Public Health, Sun Yat-sen University.

Consent to participate

All participants provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Information 1 (XLSX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Qx., Yang, Yz., Liang, Zz. et al. Time-varying effects of FOXA1 on breast cancer prognosis. Breast Cancer Res Treat 187, 867–875 (2021). https://doi.org/10.1007/s10549-021-06125-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-021-06125-7

Keywords

Search

Navigation