Skip to main content
×
Home
    • Aa
    • Aa

FOXA1 in breast cancer

  • Harikrishna Nakshatri (a1) and Sunil Badve (a2)
Abstract

Breast cancer is a heterogeneous disease and classification is important for clinical management. At least five subtypes can be identified based on unique gene expression patterns; this subtype classification is distinct from the histopathological classification. The transcription factor network(s) required for the specific gene expression signature in each of these subtypes is currently being elucidated. The transcription factor network composed of the oestrogen (estrogen) receptor α (ERα), FOXA1 and GATA3 may control the gene expression pattern in luminal subtype A breast cancers. Breast cancers that are dependent on this network correspond to well-differentiated and hormone-therapy-responsive tumours with good prognosis. In this review, we discuss the interplay between these transcription factors with a particular emphasis on FOXA1 structure and function, and its ability to control ERα function. Additionally, we discuss modulators of FOXA1 function, ERα–FOXA1–GATA3 downstream targets, and potential therapeutic agents that may increase differentiation through FOXA1.

Copyright
Corresponding author
*Corresponding author: Harikrishna Nakshatri, R4-202, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202, USA. Tel: +1 317 278 2238; Fax: +1 317 274 0396; E-mail: hnakshat@iupui.edu
References
Hide All
1Visvader J.E. and Lindeman G.J. (2006) Mammary stem cells and mammopoiesis. Cancer Research 66, 9798-9801
2Raouf A. et al. (2008) Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell 3, 109-118
3Villadsen R. (2005) In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution. APMIS 113, 903-921
4Carroll J.S. et al. (2005) Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33-43
5Laganiere J. et al. (2005) From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proceedings of the National Academy of Sciences of the United States of America 102, 11651-11656
6Eeckhoute J. et al. (2007) Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Research 67, 6477-6483
7Costa R.H., Grayson D.R. and Darnell J.E. Jr (1989) Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Molecular and Cellular Biology 9, 1415-1425
8Lai E. et al. (1990) HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes and Development 4, 1427-1436
9Lai E. et al. (1991) Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes and Development 5, 416-427
10Kaestner K.H. (2000) The hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism. Trends in Endocrinology and Metabolism 11, 281-285
11Matusik R.J. et al. (2008) Prostate epithelial cell fate. Differentiation 76, 682-698
12Panowski S.H. et al. (2007) PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 447, 550-555
13Cirillo L.A. et al. (2002) Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Molecular Cell 9, 279-289
14Clark K.L. et al. (1993) Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412-420
15Cirillo L.A. and Zaret K.S. (2007) Specific interactions of the wing domains of FOXA1 transcription factor with DNA. Journal of Molecular Biology 366, 720-724
16Qian X. and Costa R.H. (1995) Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting. Nucleic Acids Research 23, 1184-1191
17Achatz G. et al. (1997) Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression. Molecular and Cellular Biology 17, 4914-4932
18Kim J.Y. et al. (2004) Orphan nuclear receptor small heterodimer partner represses hepatocyte nuclear factor 3/Foxa transactivation via inhibition of its DNA binding. Molecular Endocrinology 18, 2880-2894
19Gao N. et al. (2003) The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Molecular Endocrinology 17, 1484-1507
20Minoo P. et al. (2007) Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Molecular and Cellular Biology 27, 2155-2165
21Minoo P. et al. (2008) SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains. Nucleic Acids Research 36, 179-188
22Sekiya T. and Zaret K.S. (2007) Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Molecular Cell 28, 291-303
23Kouzarides T. (2007) Chromatin modifications and their function. Cell 128, 693-705
24Lupien M. et al. (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958-970
25Li B., Carey M. and Workman J.L. (2007) The role of chromatin during transcription. Cell 128, 707-719
26Klose R.J. et al. (2007) The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889-900
27Christensen J. et al. (2007) RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063-1076
28Iwase S. et al. (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077-1088
29Yamane K. et al. (2007) PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Molecular Cell 25, 801-812
30Kouros-Mehr H. et al. (2006) GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127, 1041-1055
31Asselin-Labat M.L. et al. (2007) Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nature Cell Biology 9, 201-209
32Badve S. et al. (2007) FOXA1 expression in breast cancer correlation with luminal subtype A and survival. Clinical Cancer Research 13, 4415-4421
33Clarke R.B. et al. (1997) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Research 57, 4987-4991
34Varley C.L. et al. (2008) FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell Death and Differentiation 16, 103-114
35Jacob A., Budhiraja S. and Reichel R.R. (1999) The HNF-3alpha transcription factor is a primary target for retinoic acid action. Experimental Cell Research 250, 1-9
36Doane A.S. et al. (2006) An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25, 3994-4008
37Naderi A. and Hughes-Davies L. (2008) A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia 10, 542-548
38Sinner D. et al. (2004) Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 131, 3069-3080
39Schuettengruber B. et al. (2007) Genome regulation by polycomb and trithorax proteins. Cell 128, 735-745
40Bracken A.P. et al. (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes and Development 20, 1123-1136
41Lee T.I. et al. (2006) Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125, 301-313
42Schneider J. et al. (2006) Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer. International Journal of Cancer 119, 2974-2979
43Wilson B.J. and Giguere V. (2008) Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway. Molecular Cancer 7, 49
44Eeckhoute J. et al. (2006) A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes and Development 20, 2513-2526
45Su J.L. et al. (2007) Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. Journal of Biological Chemistry 282, 19385-19398
46Jonckheere N. et al. (2007) The human mucin MUC4 is transcriptionally regulated by caudal-related homeobox, hepatocyte nuclear factors, forkhead box A, and GATA endodermal transcription factors in epithelial cancer cells. Journal of Biological Chemistry 282, 22638-22650
47Gao N. et al. (2005) Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation. Development 132, 3431-3443
48Korkmaz K.S. et al. (2000) Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens. Gene 260, 25-36
49Kusumegi T. et al. (2004) BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens. Journal of Biochemical and Molecular Toxicology 18, 1-11
50Dong J.T. (2001) Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer and Metastasis Reviews 20, 173-193
51Holmes K. et al. (2008) Nkx3–1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. Cancer Research 68, 7380-7385
52Gelmann E.P., Bowen C. and Bubendorf L. (2003) Expression of NKX3.1 in normal and malignant tissues. Prostate 55, 111-117
53Pestalozzi B.C. et al. (2008) Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. Journal of Clinical Oncology 26, 3006-3014
54Habashy H.O. et al. (2008) Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance. European Journal of Cancer 44, 1541-1551
55Bretschneider N. et al. (2008) Estrogen induces repression of the breast cancer and salivary gland expression gene in an estrogen receptor alpha-dependent manner. Cancer Research 68, 106-114
56Frasor J. et al. (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144, 4562-4574
57Ben-Porath I. et al. (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genetics 40, 499-507
58Williamson E.A. et al. (2006) BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1). Oncogene 25, 1391-1399
59Prall O.W. et al. (1997) Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. Journal of Biological Chemistry 272, 10882-10894
60Perou C.M. et al. (2000) Molecular portraits of human breast tumours. Nature 406, 747-752
61Badve S. and Nakshatri H. (2009) Oestrogen receptor-positive breast cancer: towards bridging histopathologic and molecular classifications. Journal of Clinical Pathology 62, 6-12
62Carey L.A. et al. (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. The Journal of the American Medical Association 295, 2492-2502
63Thorat M.A. et al. (2007) FOXA1 expression in breast cancer is associated with Luminal subtype and good prognosis. Journal of Clinical Pathology 61, 327–32
64Yamaguchi N. et al. (2008) FoxA1 as a lineage-specific oncogene in luminal type breast cancer. Biochemical and Biophysical Research Communications 365, 711-717
65Conlin A.K. and Seidman A.D. (2007) Use of the Oncotype DX 21-gene assay to guide adjuvant decision making in early-stage breast cancer. Molecular Diagnosis and Therapy 11, 355-360
66Paik S. et al. (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. Journal of Clinical Oncology 24, 3726-3734
67Bhat-Nakshatri P. et al. (2008) AKT alters genome-wide estrogen receptor {alpha} binding and impacts estrogen signaling in breast cancer. Molecular and Cellular Biology 28, 7487-7503
68Sayeed A. et al. (2007) Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Research 67, 7746-7755
69van Agthoven T. et al. (2008) Functional identification of genes causing estrogen independence of human breast cancer cells. Breast Cancer Research and Treatment Mar 21; [Epub ahead of print]
70Sotiriou C. et al. (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. Journal of the National Cancer Institute 98, 262-272
71Loi S. et al. (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. Journal of Clinical Oncology 25, 1239-1246
72Wolf I. et al. (2007) FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer. International Journal of Cancer 120, 1013-1022
73Roman S.D. et al. (1993) Estradiol induction of retinoic acid receptors in human breast cancer cells. Cancer Research 53, 5940-5945
74Veronesi U. et al. (2006) Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Annals of Oncology 17, 1065-1071
75Qian X. et al. (1995) Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription. Molecular and Cellular Biology 15, 1364-1376
Sotiriou C. and Piccart M.J. (2007) Taking gene expression profiling to the clinic; when will molecular signatures become relevant to patient care? Nature Reviews Cancer 7, 545-553
Andre F. and Pusztai L. (2006) Molecular classification of breast cancer; implications for selection of adjuvant chemotherapy. Nature Clinical Practice Oncology 3, 621-632

The Cancer Trials Support Unit (CTSU) supports a national network of physicians to participate in National Cancer Institute (NCI)-sponsored Phase III clinical trials:

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 21
Total number of PDF views: 79 *
Loading metrics...

Abstract views

Total abstract views: 346 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd October 2017. This data will be updated every 24 hours.