Showing papers by "Eric R. Fearon published in 2002"

The SLUG Zinc-Finger Protein Represses E-Cadherin in Breast Cancer

Abstract: Loss of expression of the E-cadherin cell-cell adhesion molecule is important in carcinoma development and progression. Because previous data suggest that loss of E-cadherin expression in breast carcinoma may result from a dominant transcriptional repression pathway acting on the E-cadherin proximal promoter, we pursued studies of cis sequences and transcription factors regulating E-cadherin expression in breast cancer cells. E-box elements in the E-cadherin promoter were found to play a critical negative regulatory role in E-cadherin gene transcription in breast cancer cell lines lacking E-cadherin transcription. The E-box elements had a minimal role in E-cadherin transcription in breast cancer cell lines expressing E-cadherin. Two zinc-finger transcription factors known to bind E-box elements, SLUG and SNAIL, repressed E-cadherin-driven reporter gene constructs containing wild-type promoter sequences but not those with mutations in the E-box elements. Additionally, both SLUG and SNAIL repressed endogenous E-cadherin expression. These findings suggest SLUG and SNAIL are potential repressors of E-cadherin transcription in carcinomas lacking E-cadherin expression. Analysis of the expression patterns of SLUG, SNAIL, and E-cadherin in breast cancer cell lines demonstrated that expression of SLUG was strongly correlated with loss of E-cadherin transcripts. Taken together, the data indicate the E-box elements in the proximal E-cadherin promoter are critical in transcriptional repression of the E-cadherin gene, and SLUG is a likely in vivo repressor of E-cadherin in breast cancer.

Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas.

Abstract: Biologically and clinically meaningful tumor classification schemes have long been sought. Some malignant epithelial neoplasms, such as those in the thyroid and endometrium, exhibit more than one pattern of differentiation, each associated with distinctive clinical features and treatments. In other tissues, all carcinomas, regardless of morphological type, are treated as though they represent a single disease. To better understand the biological and clinical features seen in the four major histological types of ovarian carcinoma (OvCa), we analyzed gene expression in 113 ovarian epithelial tumors using oligonucleotide microarrays. Global views of the variation in gene expression were obtained using PCA. These analyses show that mucinous and clear cell OvCas can be readily distinguished from serous OvCas based on their gene expression profiles, regardless of tumor stage and grade. In contrast, endometrioid adenocarcinomas show significant overlap with other histological types. Although high-stage/grade tumors are generally separable from low-stage/grade tumors, clear cell OvCa has a molecular signature that distinguishes it from other poor-prognosis OvCas. Indeed, 73 genes, expressed 2- to 29-fold higher in clear cell OvCas compared with each of the other OvCa types, were identified. Collectively, the data indicate that gene expression patterns in ovarian adenocarcinomas reflect both morphological features and biological behavior. Moreover, these studies provide a foundation for the development of new type-specific diagnostic strategies and treatments for ovarian cancer.

Cadherin and catenin alterations in human cancer.

Abstract: Among the hallmarks of cancer are defective cell-cell and cell-matrix adhesion. Alterations in cadherin-catenin complexes likely have a major contributing role in cell-adhesion defects in carcinomas arising in many different tissues. E-cadherin, the prototypic member of the cadherin transmembrane protein family, regulates cell adhesion by interacting with E-cadherin molecules on opposing cell surfaces. E-cadherin's function in cell adhesion is also critically dependent on its ability to interact through its cytoplasmic domain with catenin proteins. A diverse collection of defects alter cadherin-catenin function in cancer cells, including loss-of-function mutations and defects in the expression of E-cadherin and certain catenins, such as alpha-catenin. Although there is much evidence that beta-catenin is deregulated in cancer as a result of inactivating mutations in the APC and AXIN tumor-suppressor proteins and gain-of-function mutations in beta-catenin itself, the principal consequences of beta-catenin deregulation in cancer appear to be largely distinct from the effects attributable to inactivation of E-cadherin or alpha-catenin. In this review, we highlight some of the specific genetic and epigenetic defects responsible for altered cadherin and catenin function in cancer, as well as potential contributions of cadherin-catenin alterations to the cancer process.

Role of β-Catenin/T-Cell Factor-Regulated Genes in Ovarian Endometrioid Adenocarcinomas

Abstract: In various cancers, inactivating mutations in the adenomatous polyposis coli or Axin tumor suppressor proteins or activating mutations in β-catenin's amino-terminal domain elevate β-catenin levels, resulting in marked effects on T-cell factor (TCF)-regulated transcription. Several candidate β-catenin/TCF-regulated genes in cancer have been proposed. Expression of a few of these genes has been studied in primary human cancers, but most studies have focused on colon cancers and not on other cancer types that harbor mutational defects in adenomatous polyposis coli, AXIN, or β-catenin. Mutations leading to β-catenin deregulation are found in nearly half of ovarian endometrioid adenocarcinomas (OEAs). We report here on the expression of 6 candidate β-catenin/TCF-regulated genes in a panel of 44 primary OEAs, more than a third of which carry demonstrable defects in β-catenin regulation. Using quantitative assays of gene expression, we found significantly elevated expression of the MMP-7, CCND1 ( Cyclin D1 ), CX43 ( Connexin 43 ), PPAR-δ , and ITF2 genes in OEAs with deregulated β-catenin. This correlation was not observed for c -myc , another putative β-catenin/TCF-regulated gene. Immunohistochemical studies confirmed that overexpression of cyclin D1 and MMP-7 was highly associated with nuclear accumulation of β-catenin and mutational defects of the Wnt/β-catenin/TCF-signaling pathway. Our findings indicate cyclin D1, MMP-7, connexin 43, PPAR-δ, and ITF-2, likely play important roles in the pathogenesis of those OEAs that manifest defects in β-catenin regulation.