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01-02-2012 | Preclinical Study

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

Authors: Rutika J. Mehta, Rohit K. Jain, Samuel Leung, Jennifer Choo, Torsten Nielsen, David Huntsman, Harikrishna Nakshatri, Sunil Badve

Published in: Breast Cancer Research and Treatment | Issue 3/2012

Abstract

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.

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Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752PubMedCrossRef

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(1):33–43PubMedCrossRef

Laganiere J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguere V (2005) From the cover: location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc Natl Acad Sci 102(33):11651–11656PubMedCrossRef

Costa RH, Grayson DR, Darnell JE Jr (1989) Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol 9(4):1415–1425PubMed

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(1):27–33PubMedCrossRef

Clark KL, Halay ED, Lai E, Burley SK (1993) Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364(6436):412–420PubMedCrossRef

Carroll JS, Brown M (2006) Estrogen receptor target gene: an evolving concept. Mol Endocrinol 20(8):1707–1714PubMedCrossRef

Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (2006) GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127(5):1041–1055PubMedCrossRef

Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, Lindeman GJ, Visvader JE (2007) GATA-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9(2):201–209PubMedCrossRef

10.

Ademuyiwa FO, Thorat MA, Jain RK, Nakshatri H, Badve S (2010) Expression of Forkhead-box protein A1, a marker of luminal A type breast cancer, parallels low Oncotype DX 21-gene recurrence scores. Mod Pathol 23(2):270–275PubMedCrossRef

11.

Wolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP (2007) FOXA1: growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer 120(5):1013–1022PubMedCrossRef

12.

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(9):1391–1399PubMedCrossRef

13.

West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, Zuzan H, Olson JA Jr, Marks JR, Nevins JR (2001) Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci 98(20):11462–11467PubMedCrossRef

14.

Thorat MA, Marchio C, Morimiya A, Savage K, Nakshatri H, Reis-Filho JS, Badve S (2008) Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis. J Clin Pathol 61(3):327–332PubMedCrossRef

15.

Badve S, Turbin D, Thorat MA, Morimiya A, Nielsen TO, Perou CM, Dunn S, Huntsman DG, Nakshatri H (2007) FOXA1 expression in breast cancer—correlation with luminal subtype A and survival. Clin Cancer Res 13(15 Pt 1):4415–4421PubMedCrossRef

16.

Nakshatri H, Badve S (2007) FOXA1 as a therapeutic target for breast cancer. Expert Opin Ther Targets 11(4):507–514PubMedCrossRef

17.

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(3):R40PubMedCrossRef

18.

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(11):1541–1551PubMedCrossRef

19.

Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA (2004) Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol 22(9):1630–1637PubMedCrossRef

20.

Lohrisch C, Jackson J, Jones A, Mates D, Olivotto IA (2000) Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer. J Clin Oncol 18(15):2828–2835PubMed

21.

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847PubMedCrossRef

22.

Parker RL, Huntsman DG, Lesack DW, Cupples JB, Grant DR, Akbari M, Gilks CB (2002) Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol 117(5):723–728PubMedCrossRef

23.

Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750PubMedCrossRef

24.

Cheang MC, Treaba DO, Speers CH, Olivotto IA, Bajdik CD, Chia SK, Goldstein LC, Gelmon KA, Huntsman D, Gilks CB, Nielsen TO, Gown AM (2006) Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24(36):5637–5644PubMedCrossRef

25.

Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K (2008) Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 26(35):5697–5704PubMedCrossRef

26.

Crabb SJ, Bajdik CD, Leung S, Speers CH, Kennecke H, Huntsman DG, Gelmon KA (2008) Can clinically relevant prognostic subsets of breast cancer patients with four or more involved axillary lymph nodes be identified through immunohistochemical biomarkers? A tissue microarray feasibility study. Breast Cancer Res 10(1):R6PubMedCrossRef

27.

Voduc D, Cheang M, Nielsen T (2008) GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol Biomarkers Prev 17(2):365–373PubMedCrossRef

28.

Wong MP, Cheang M, Yorida E, Coldman A, Gilks CB, Huntsman D, Berean K (2008) Loss of desmoglein 1 expression associated with worse prognosis in head and neck squamous cell carcinoma patients. Pathology 40(6):611–616PubMedCrossRef

29.

Eeckhoute J, Lupien M, Meyer CA, Verzi MP, Shivdasani RA, Liu XS, Brown M (2009) Cell-type selective chromatin remodeling defines the active subset of FOXA1-bound enhancers. Genome Res 19(3):372–380PubMedCrossRef

30.

Badve S, Nakshatri H (2009) Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications. J Clin Pathol 62(1):6–12PubMedCrossRef

31.

Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald WL (2006) An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25(28):3994–4008PubMedCrossRef

32.

Yamaguchi N, Ito E, Azuma S, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Tatsuta K, Inoue J, Semba K, Watanabe S (2008) FOXA1 as a lineage-specific oncogene in luminal type breast cancer. Biochem Biophys Res Commun 365(4):711–717PubMedCrossRef

33.

Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26(5):711–724PubMedCrossRef

34.

Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, Fehrenbacher L, Lin Gomez S, Miles S, Neugut AI (2010) Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 28(27):4120–4128PubMedCrossRef

35.

Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312PubMedCrossRef

Title: FOXA1 is an independent prognostic marker for ER-positive breast cancer
Authors: Rutika J. Mehta
Rohit K. Jain
Samuel Leung
Jennifer Choo
Torsten Nielsen
David Huntsman
Harikrishna Nakshatri
Sunil Badve
Publication date: 01-02-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1482-6

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