FOXA1 Is a Potential Oncogene in Anaplastic Thyroid Carcinoma

Purpose: FOXA1 is a mammalian endodermal transcription factor belonging to the human forkhead box gene family that plays a role in certain tumor types. Here, we investigated the potential role of FOXA1 in human thyroid carcinomas. Experimental Design: We examined the level of FOXA1 expression and gene copy number by immunohistochemistry and fluorescence in situ hybridization, respectively, in a cohort of benign and malignant thyroid tumors. In addition, we examined the role of FOXA1 in the proliferation of an undifferentiated thyroid carcinoma cell line by short hairpin RNA-mediated silencing. Results: We show that FOXA1 is overexpressed in human anaplastic thyroid carcinomas (ATC). In addition, we identify FOXA1 DNA copy number gain within the 14q21.1 locus in both an ATC cell line and human ATC cases. Silencing of FOXA1 in an ATC cell line causes G1 growth arrest and reduction of cell proliferation. Moreover, we observe a potential link between FOXA1 and the cell cycle machinery by identifying p27kip1 up-regulation on FOXA1 silencing. Conclusions:FOXA1 is overexpressed in aggressive thyroid cancers and involved in cell cycle progression in an ATC cell line. Therefore, FOXA1 may be an important oncogene in thyroid tumorigenesis and a potential new therapeutic target for the treatment of anaplastic thyroid cancers.

[1]  Christopher Korch,et al.  Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. , 2008, The Journal of clinical endocrinology and metabolism.

[2]  Parantu K. Shah,et al.  Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression , 2008, Molecular systems biology.

[3]  Clifford A. Meyer,et al.  FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific Transcription , 2008, Cell.

[4]  M. Rivera,et al.  Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms , 2008, Modern Pathology.

[5]  J. Inoue,et al.  FoxA1 as a lineage-specific oncogene in luminal type breast cancer. , 2008, Biochemical and biophysical research communications.

[6]  E. Lam,et al.  The emerging roles of forkhead box (Fox) proteins in cancer , 2007, Nature Reviews Cancer.

[7]  Steven J. M. Jones,et al.  Identification of molecular markers altered during transformation of differentiated into anaplastic thyroid carcinoma. , 2007, Archives of surgery.

[8]  P. Sicinski,et al.  Duality of p27Kip1 function in tumorigenesis. , 2007, Genes & development.

[9]  Jérôme Eeckhoute,et al.  Positive Cross-Regulatory Loop Ties GATA-3 to Estrogen Receptor α Expression in Breast Cancer , 2007 .

[10]  Carl W. Miller,et al.  FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer , 2006, International journal of cancer.

[11]  S. Y. Park,et al.  Epidermal growth factor receptor status in anaplastic thyroid carcinoma , 2006, Journal of Clinical Pathology.

[12]  P. Sicinski,et al.  Duality of p27 Kip1 function in tumorigenesis , 2007 .

[13]  Ashish Rajput,et al.  Anaplastic Thyroid Carcinoma: Expression Profile of Targets for Therapy Offers New Insights for Disease Treatment , 2007, Annals of Surgical Oncology.

[14]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[15]  Jérôme Eeckhoute,et al.  A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. , 2006, Genes & development.

[16]  K. Kaestner,et al.  The Foxa family of transcription factors in development and metabolism , 2006, Cellular and Molecular Life Sciences CMLS.

[17]  Myles A Brown,et al.  Estrogen receptor target gene: an evolving concept. , 2006, Molecular endocrinology.

[18]  S. Asa,et al.  Pathogenetic mechanisms in thyroid follicular-cell neoplasia , 2006, Nature Reviews Cancer.

[19]  Gerard M Doherty,et al.  Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2006, Thyroid : official journal of the American Thyroid Association.

[20]  E. Williamson,et al.  BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1 , 2006, Oncogene.

[21]  Céline Lefebvre,et al.  From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Clifford A. Meyer,et al.  Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1 , 2005, Cell.

[23]  Klaus H. Kaestner,et al.  The initiation of liver development is dependent on Foxa transcription factors , 2005, Nature.

[24]  Myles Brown,et al.  Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-alpha and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT. , 2005, Molecular endocrinology.

[25]  Y. Nikiforov.  Editorial: anaplastic carcinoma of the thyroid--will aurora B light a path for treatment? , 2005, The Journal of clinical endocrinology and metabolism.

[26]  Céline Lefebvre,et al.  Location analysis of estrogen receptor target promoters reveals that FOXA 1 defines a domain of the estrogen response , 2005 .

[27]  A. D. De Marzo,et al.  Practical methods for tissue microarray construction. , 2005, Methods in molecular medicine.

[28]  J. Whitsett,et al.  Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. , 2004, Gene expression patterns : GEP.

[29]  R. DeLellis.  Pathology and genetics of tumours of endocrine organs , 2004 .

[30]  K. Chin,et al.  Anaplastic thyroid cancer: cytogenetic patterns by comparative genomic hybridization. , 2003, Thyroid : official journal of the American Thyroid Association.

[31]  J. Shah,et al.  Genome-wide appraisal of thyroid cancer progression. , 2002, The American journal of pathology.

[32]  G. Daniels,et al.  Radioactive iodine lobe ablation as an alternative to completion thyroidectomy for follicular carcinoma of the thyroid. , 2002, Thyroid : official journal of the American Thyroid Association.

[33]  G. Viglietto,et al.  Understanding p27kip1 Deregulation in Cancer: Downregulation or Mislocalizaiton? , 2002, Cell cycle.

[34]  David E. Misek,et al.  The Hepatocyte Nuclear Factor 3 α Gene, HNF3α (FOXA1), on Chromosome Band 14q13 Is Amplified and Overexpressed in Esophageal and Lung Adenocarcinomas , 2002 .

[35]  Frank R. Lin,et al.  Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. , 2002, Molecular cell.

[36]  Y. Nakamura,et al.  Identification of target genes within an amplicon at 14q12‐q13 in esophageal squamous cell carcinoma , 2001, Genes, chromosomes & cancer.

[37]  C. Larsson,et al.  Gain of 1q and loss of 9q21.3‐q32 are associated with a less favorable prognosis in papillary thyroid carcinoma , 2001, Genes, chromosomes & cancer.

[38]  M. Loda,et al.  Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN , 2000, Molecular and Cellular Biology.

[39]  G. Viglietto,et al.  Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells. , 1999, The Journal of clinical investigation.

[40]  K. Franssila,et al.  DNA copy number changes in thyroid carcinoma. , 1999, The American journal of pathology.

[41]  K. Lam,et al.  Anaplastic carcinoma of the thyroid. , 1999, American journal of surgery.

[42]  K. Ain.  Anaplastic thyroid carcinoma: a therapeutic challenge. , 1999, Seminars in surgical oncology.

[43]  P. Wollan,et al.  Expression of p27kip1 and Ki-67 in benign and malignant thyroid tumors. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[44]  M. Loda,et al.  Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas , 1997, Nature Medicine.

[45]  J. R. Coleman,et al.  Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. , 1996, Genes & development.