Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

Integrated Analysis of Gene Expression, CpG Island Methylation, and Gene Copy Number in Breast Cancer Cells by Deep Sequencing

We used deep sequencing technology to profile the transcriptome, gene copy number, and CpG island methylation status simultaneously in eight commonly used breast cell lines to develop a model for how these genomic features are integrated in estrogen receptor positive (ER+) and negative breast cancer. Total mRNA sequence, gene copy number, and genomic CpG island methylation were carried out using the Illumina Genome Analyzer. Sequences were mapped to the human genome to obtain digitized gene expression data, DNA copy number in reference to the non-tumor cell line (MCF10A), and methylation status of 21,570 CpG islands to identify differentially expressed genes that were correlated with methylation or copy number changes. These were evaluated in a dataset from 129 primary breast tumors. Gene expression in cell lines was dominated by ER-associated genes. ER+ and ER− cell lines formed two distinct, stable clusters, and 1,873 genes were differentially expressed in the two groups. Part of chromosome 8 was deleted in all ER− cells and part of chromosome 17 amplified in all ER+ cells. These loci encoded 30 genes that were overexpressed in ER+ cells; 9 of these genes were overexpressed in ER+ tumors. We identified 149 differentially expressed genes that exhibited differential methylation of one or more CpG islands within 5 kb of the 5′ end of the gene and for which mRNA abundance was inversely correlated with CpG island methylation status. In primary tumors we identified 84 genes that appear to be robust components of the methylation signature that we identified in ER+ cell lines. Our analyses reveal a global pattern of differential CpG island methylation that contributes to the transcriptome landscape of ER+ and ER− breast cancer cells and tumors. The role of gene amplification/deletion appears to more modest, although several potentially significant genes appear to be regulated by copy number aberrations

Decreased expression of hyaluronan synthase 1 and 2 associates with poor prognosis in cutaneous melanoma

Background Hyaluronan is a large extracellular matrix molecule involved in several biological processes such as proliferation, migration and invasion. In many cancers, hyaluronan synthesis is altered, which implicates disease progression and metastatic potential. We have previously shown that synthesis of hyaluronan and expression of its synthases 1–2 (HAS1-2) decrease in cutaneous melanoma, compared to benign melanocytic lesions. Methods In the present study, we compared immunohistological staining results of HAS1 and HAS2 with clinical and histopathological parameters to investigate whether HAS1 or HAS2 has prognostic value in cutaneous melanoma. The specimens consisted of 129 tissue samples including superficial (Breslow ≤ 1 mm) and deep (Breslow > 4 mm) melanomas and lymph node metastases. The differences in immunostainings were analysed with non-parametric Mann–Whitney U test. Associations between immunohistological staining results and clinical parameters were determined with the χ2 test. Survival between patient groups was compared by the Kaplan-Meier method using log rank test and Cox’s regression model was used for multivariate analyses. Results The expression of HAS1 and HAS2 was decreased in deep melanomas and metastases compared to superficial melanomas. Decreased immunostaining of HAS2 in melanoma cells was significantly associated with several known unfavourable histopathologic prognostic markers like increased mitotic count, absence of tumor infiltrating lymphocytes and the nodular subtype. Furthermore, reduced HAS1 and HAS2 immunostaining in the melanoma cells was associated with increased recurrence of melanoma (p = 0.041 and p = 0.006, respectively) and shortened disease- specific survival (p = 0.013 and p = 0.001, respectively). Conclusions This study indicates that reduced expression of HAS1 and HAS2 is associated with melanoma progression and suggests that HAS1 and HAS2 have a prognostic significance in cutaneous melanoma.published versionpeerReviewe

Abstract 2458: The expression of hyaluronan and hyaluronidases in cutaneous melanoma

Abstract Aberrant hyaluronan expression implicates aggressive disease progression and metastatic potential in many cancers. In tumors originating from simple epithelium, hyaluronan amount is increased both in the epithelial and stromal component and it correlates with patient's poor overall prognosis. The role of hyaluronan degrading enzymes (hyaluronidases, HYAL1-2) in cancer progression is controversial. Hyaluronidases are proposed to be both tumor suppressors and tumor promoters. In this retrospective study, we characterized the expression levels of HYAL1 and HYAL2 and correlated their expression to hyaluronan in the different stages of primary skin melanoma as well as in metastatic melanoma. Superfically (pT1) and deeply (pT4) invasive melanoma (Breslow &amp;lt; 1mm (n=18) and Breslow &amp;gt; 4mm (n=18)), in situ melanoma (n=17), lymph node metastasis (n=19), dysplastic nevi (n=28) and benign nevi samples (n=29) were analyzed for hyaluronan staining and HYAL1 and HYAL2 immunoreactivity (ABCAM antibodies) in paraffin tissue sections. Stainings were evaluated for their intensity and coverage. The tissue area for hyaluronan and HYAL1/HYAL2 positive staining was estimated with a five-level scoring from 0-4 and the staining intensity of melanocytic cells was evaluated with a four-level scoring (0-3; no color, weak, moderate and strong) by two independent observers. Compared to benign nevi and in situ melanoma, the cell-associated hyaluronan staining coverage and intensity were clearly reduced in the invasive part of melanoma with advanced Breslow depth. Strong hyaluronan staining intensity was detected in 36% of in situ melanoma cases and in 21% of superficial melanoma (Breslow &amp;lt; 1mm) cases, while in the deeply invasive melanoma group (Breslow &amp;gt; 4mm), only 6% of cases showed strong hyaluronan staining intensity. In addition, in lymph node metastases the melanoma cells showed low hyaluronan staining intensity or were totally hyaluronan negative. However, the tumor stroma was highly hyaluronan positive in all groups. HYAL1 immunoreactivity was found in melanocytic cells both in benign nevi and melanoma samples while the tumor stromal cells were negative. The coverage of HYAL2 immunoreactivity was parallel to HYAL1, although its staining intensity was lower than that of HYAL1. Our results suggest that hyaluronan content is clearly decreased in invasive primary and metastatic melanoma compared to benign nevi. The results from hyaluronan stainings will be compared with clinical follow-up data to study the prognostic value of hyaluronan in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2458. doi:1538-7445.AM2012-2458</jats:p