Showing papers by "David G. Ginzinger published in 2005"

Troglitazone, the Peroxisome Proliferator-Activated Receptor-γ Agonist, Induces Antiproliferation and Redifferentiation in Human Thyroid Cancer Cell Lines

Abstract: Troglitazone is a potent agonist for the peroxisome proliferator-activated receptor-γ (PPARγ) that is a ligandactivated transcription factor regulating cell differentiation and growth. PPARγ may play a role in thyroid carcinogenesis since PAX8-PPARγ1 chromosomal translocations are commonly found in follicular thyroid cancers. We investigated the antiproliferative and redifferentiation effects of troglitazone in 6 human thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hurthle cell), and ARO82-1 (anaplastic) cell lines. PPARγ was expressed variably in these cell lines. FTC-236 and FTC-238 had a rearranged chromosome at 3p25, possibly implicating the involvement of the PPARγ encoding gene whereas the other cell lines did not. Troglitazone significantly inhibited cell growth by cell cycle arrest and apoptotic cell death. PPARγ overexpression did not appear to be a prerequisite for a response to treatment with troglitazone. Troglitazone also downregulated surface exp...

Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling.

Abstract: Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85%) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7 . Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3σ (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo .

High-resolution analysis of genomic alterations and human papillomavirus integration in anal intraepithelial neoplasia.

Abstract: Anal intraepithelial neoplasia (AIN) is the likely precursor to anal cancer. AIN is associated with human papillomavirus (HPV) infection, and HPV-associated genomic instability may play an important role in the progression of squamous intraepithelial neoplasia to cancer. Microarray-based comparative genome hybridization (aCGH) was performed on DNA from AIN specimens to determine the host genomic alterations and their correlation with HPV DNA integration or rearrangement. Of 27 high-grade AIN specimens tested by CGH, 8 (30%) showed regional DNA copy number abnormalities (CNAs). Five additional cases previously identified by chromosome CGH to carry CNAs were reanalyzed by aCGH and pooled with the 8 new cases for analysis. The most common regions of gain were on chromosome arms 1p, 1q, 3q, 8p, and 20q. The most common regions of loss were on chromosome arms 2q, 7q, 11p, 11q, and 15q. HPV16 DNA integration or rearrangement correlated with CNAs in host cell DNA (P = 0.007). Although aCGH can resolve amplicons at the 1- to 2-megabase (Mb) regional resolution, the most common alteration on chromosome 3 could only be resolved to a 75-Mb region from 3q21 to qtel. Our data suggest that there may be several oncogenes in this region that are coactivated to contribute to progression to high-grade AIN.

Ethnic and racial differences in prostate stromal estrogen receptor α

Abstract: BACKGROUND Prostate cancer incidence and mortality rates vary widely among individuals of different ethnic/racial groups. We identified a relationship between a subset of genes and race/ethnicity using gene expression profiling. Estrogen receptor α (ERα) was selected for confirmation due to its plausible biological role in cancer susceptibility. METHODS Quantitative polymerase chain reaction (Q-PCR) was used to verify gene expression results. Protein levels of ERα were determined by quantitative immunohistochemistry in a large-scale tissue microarray study (n = 183). RESULTS ERα was significantly higher in stroma of Hispanic and Asian men than in Caucasian (P < 0.0001) and African American men (P < 0.0002), who are at higher risk for prostate cancer. In addition, large differences were seen in Q-PCR levels of ERα in prostate tissues of organ donors 16–29 years old who had no evidence of cancer. CONCLUSIONS ERα exhibits variable expression in men of difference racial/ethnic background. Understanding the molecular basis for these differences may form the basis for prostate cancer prevention strategies with widespread public health impact. © 2005 Wiley-Liss, Inc.