p53 is a 53-kDa nuclear protein that is associated with malignant transformation in several tumor model systems. In a survey of 134 human carcinomas, sarcomas, leukemias, and lymphomas obtained at surgery or from peripheral blood, we found rearrangements of the p53 gene only in osteogenic sarcomas (3 of 6 osteogenic sarcomas examined). Normal tissue from one of these patients had an unrearranged gene, indicating that the genetic abnormality in the tumor was acquired. Two of the sarcomas with rearranged genes expressed levels of p53 protein that were elevated relative to other tumors. Rearranged p53 genes were also found in human osteogenic sarcoma cell lines.

The CCAAT/enhancer binding protein ␣ (C/EBP␣) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBP␣ function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBP␣ gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelog- IntroductionThe CCAAT/enhancer binding protein ␣ (C/EBP␣) belongs to a family of proteins that possess a bipartite DNA-binding domain composed of a positively charged basic (b) region that contacts the DNA and a leucine zipper (ZIP) in the C terminus that mediates dimerization. 1 The less-conserved N terminus contains regulatory and transactivation domains. 2-5 C/EBP␣ is expressed in a number of tissues, most prominently in the highly differentiated cells of the liver, white and brown adipose, lung, and myeloid-lineage cells. [6][7][8][9] It has also been detected in the adrenal gland, skin, pancreas, prostate, differentiated enterocytes in the intestine, and, during follicular development, the ovary. [9][10][11][12] C/EBP␣ is proposed to be a regulator of energy metabolism and transcriptionally activates the promoters of energy-related genes such as GLUT4 and PEPCK in hepatocytes and adipocytes. [13][14][15] In myeloid cells, C/EBP␣ transcriptionally activates the promoters of the myeloid-specific receptors for the growth factors macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor. [16][17][18] Studies demonstrate that C/EBP␣ is critical for the process of terminal differentiation of adipocytes. C/EBP␣ is upregulated in adipocyte differentiation, and blocking its expression halts differentiation of preadipocytes into adipocytes, while overexpression induces differentiation and inhibits proliferation. [19][20][21][22][23] Also, overexpression of C/EBP␣ induces differentiation of myeloid leukemia cell lines and inhibits the proliferation of a number of cell lines and tumor cells. [24][25][26][27] The inhibition of proliferation is partly due to the ability of C/EBP␣ to activate transcription and induce posttranscriptional stabilization of the cyclin-dependent kinase inhibitor p21 (WAF-1). 28,29 These studies suggest a central role for C/EBP␣ in the regulation of cell proliferation and differentiation.Targeted inactivation of C/EBP␣ in mice demonstrates its importance in the proper development and function of liver, adipose, lung, and hematopoietic tissues. 8,30,31 Within 8 hours after birth, the mice die of impaired glucose metabolism, and adipose metabolism is altered with a failure of adipocytes to accumulate lipids. 30,31 The lung shows hyperproliferati...

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Molecular defects affecting tumor-suppressor genes are an important step in the genesis of sarcomas. For example, inheritance of a defective Rb or p53 gene predisposes the carrier to develop osteosarcoma, among other malignancies. In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas. Point mutations of the p53 gene were found in 13 of 42 osteosarcomas and 1 of 8 leiomyosarcomas, and gross rearrangement of the p53 gene was demonstrated in 5 of 37 osteosarcomas. The retinoblastoma susceptibility gene (Rb) was either rearranged or deleted in 7 of 37 osteosarcomas, 1 of 7 soft-tissue sarcomas and 1 of 4 Ewing sarcomas. Remarkably, 5 of the osteosarcomas having Rb alterations also had p53 mutations. Amplification and overexpression of the MDM2 oncogene may lead to increased MDM2-p53 binding resulting in inactivation of p53 function. A two- to threefold increase in the copy number of MDM2 was detected in 7 of 37 samples, 5 of which were osteosarcomas. Amplification of the MDM2 gene occurred independently of p53 mutation; one sample having threefold amplification of MDM2 also had a p53 mutation. In summary, 34 alterations of the p53, Rb and MDM2 genes were found in 26 of 42 (62%) osteosarcomas.

ABSTRACT

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The transcription factor Forkhead-box A1 (Foxa1), a member of the FOX class of transcription factors, has been implicated in the pathogenesis of lung, esophageal and prostate cancers. We have recently identified transcriptional activation of p27 by FOXA1. In this study, we analyzed the activities and expression pattern of FOXA1 in breast cancer. Forced expression of FOXA1 inhibited clonal growth of breast cancer cell lines, and FOXA1 levels inversely correlated with growth stimuli. In the estrogen receptor (ER)-positive MCF-7 cells, FOXA1 increased p27 promoter activity and inhibited the ER pathway activity. Analysis of FOXA1 expression in breast tissue arrays revealed significantly higher expression in pure ductal carcinomas in situ compared to invasive ductal carcinomas (IDC); and in IDC, high expression of FOXA1 was associated with favorable prognostic factors. Yet, FOXA1 expression was noted in a subset of the ER-negative tumors. Taken together, our findings suggest a growth inhibitory role for FOXA1, and identify it as a novel, potential prognostic factor in breast cancer. ' 2006 Wiley-Liss, Inc.Key words: FOXA1; breast cancer; p27; estrogen receptorThe FOX class of transcription factors, now counting more than 100 members, is characterized by an evolutionary conserved 110 amino-acid DNA binding domain, known as the forkhead (FH) domain.1,2 Three FOXA proteins, FOXA1, FOXA2 and FOXA3, are currently known and each shares a conserved structure, consisting of DNA binding domain and 4 transactivating regions, 2 in the C-terminal side of the protein and 2 in its N-terminus.3-5 FOXA1 is expressed in the liver, pancreas, bladder, prostate, colon, lung as well as mammary gland and can bind to the promoters of more than 100 genes associated with metabolic processes, regulation of signaling and the cell cycle.1,2,6 In mice, embryos carrying a homozygous null mutation for FOXA1 develop normally to term but suffer from severe postnatal growth retardation and hypoglycemia followed by death between postnatal days 2 and 12. 7,8 High expression of FOXA1 has been reported in various tumors, including lung, esophageal and prostate cancer. 9,10 In prostate cancer, current data suggest a growth inhibitory role for FOXA1. While FOXA1 is expressed in both preneoplastic lesions and adenocarcinomas, its expression is associated with markers of differentiation, and transfection assays revealed that FOXA1 had an inhibitory effect on the androgen receptor. 11 Moreover, FOXA1 null prostate shows hyperplastic lesions. 11In breast cancer, studies of global gene expression revealed high expression of FOXA1 mRNA, often in association with the expression of the estrogen receptor alpha (ERa), 12,13 but also showed FOXA1 expression in a subset of ER-negative tumors.14 Among the ER-positive tumors, expression of FOXA1 mRNA was noted in tumors that showed favorable outcomes. 15 In accordance with a growth inhibitory role of FOXA1 in breast cancer, studies in MCF-7 cells suggested downregulation of FOXA1 mRNA levels following estrogen stimulat...

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