keratan-sulfate and Breast-Neoplasms

HSP90 has been studied intensively as a therapeutic target, however little is known regarding specific interactions of the large number of HSP90 client proteins. Therefore, this study investigated HSP90 client proteins sensitive to the HSP90 inhibitor geldanamycin in tumour and healthy breast tissue.. Co-immunoprecipitation and SDS-PAGE were used to investigate protein interactions. Western blotting and LC-MS were used to infer protein identities.. HSP90 client proteins were observed in 7 out of 11 breast cancer patients. Further experiments inferred HSP40, -56/FKBP52, -60, -70, -105 and lumican to associate with HSP90 and to belong to this group of geldanamycin-sensitive proteins. In one patient, a cancer-specific group of proteins was identified. In all experiments geldanamycin resistance was observed.. HSP90 differentially associated with client proteins and this was patient dependent. Geldanamycin resistance and lack of HSP90 client protein expression may limit clinical applications of HSP90 inhibitors.

Topics: Antibiotics, Antineoplastic; Benzoquinones; Breast Neoplasms; Chondroitin Sulfate Proteoglycans; Female; HSP90 Heat-Shock Proteins; Humans; Immunoprecipitation; Keratan Sulfate; Lactams, Macrocyclic; Lumican; Molecular Targeted Therapy; Protein Isoforms

The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer.. We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)).. In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (P trend

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Case-Control Studies; Chondroitin Sulfate Proteoglycans; Decorin; England; Extracellular Matrix Proteins; Female; Genetic Variation; Heterozygote; Homozygote; Humans; Keratan Sulfate; Lumican; Middle Aged; Odds Ratio; Proteoglycans; Stromal Cells; Young Adult

The composition of proteoglycans and their changes during malignant transformation are important factors influencing adhesive properties and mitotic activity of tumor cells. In this study, expression level of different proteoglycans (decorin, syndecan-1, lumican, glypican-1, and aggrecan) in tumors and normal human breast tissue was investigated. Multiplex RT-PCR data revealed different expression changes for different proteoglycans in human breast tumors--syndecan expression was activated compared to almost no expression in normal breast tissue, expression of decorin and lumican decreased 2-5- and 2-3-fold, respectively, and aggrecan transcription seems to be unaffected. A change of expression level of decorin correlated with expression of D-glucuronyl-C5-epimerase, a key enzyme responsible for the biosynthesis of idurone-containing glycosaminoglycans, possessing antimitotic activity. The results suggest that changes in decorin, lumican, and syndecan-1 expression in tumor tissue could induce a distortion of proteoglycan composition and mitotic activity of cells in human breast tumor.

Topics: Aggrecans; Breast Neoplasms; Carbohydrate Epimerases; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Female; Glypicans; Humans; Keratan Sulfate; Lumican; Proteoglycans; Syndecan-1

To examine the prognostic significance of lumican and decorin, two abundant small leucine-rich proteoglycans in breast tissue stroma.. Lumican and decorin expression was examined in a cohort of 140 invasive breast carcinomas by Western blot analysis. All cases were axillary lymph node-negative and treated by adjuvant endocrine therapy.. Lumican and decorin expression was highly correlated (r = 0.45, P < 0.0001), but although low levels of lumican were associated with large tumor size (P = 0.0496), negative estrogen receptor (P = 0.0024) and progesterone receptor status (P = 0.0116), and increased host inflammatory response (P = 0.0077), low decorin levels were associated only with large tumor size (P = 0.0496). However, using univariate analysis, low levels of lumican and decorin were both associated with a shorter time to progression (P = 0.0013 and 0.0262) and poorer survival (P = 0.001 and 0.0076). In multivariate analysis using the Cox regression model, low decorin was also shown to be an independent predictive factor for recurrence (hazard ratio 2.25: 95% confidence interval 1-5, P = 0.047) and survival (hazard ratio 3.39: 95% confidence interval 1.2-9.6, P = 0.021).. These results suggest that low levels of small leucine-rich proteoglycans in breast tumors may be associated with a worse prognosis in lymph node-negative invasive breast carcinomas and warrant further study with larger patient cohorts.

Topics: Blotting, Western; Breast Neoplasms; Chondroitin Sulfate Proteoglycans; Decorin; Disease Progression; Disease-Free Survival; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix Proteins; Female; Humans; Immunoblotting; Keratan Sulfate; Leucine; Lumican; Lymph Nodes; Prognosis; Proteoglycans; Time Factors; Treatment Outcome

Mammographic density and certain histological changes in breast tissues are both risk factors for breast cancer. However, the relationship between these factors remains uncertain. Previous studies have focused on the histology of the epithelial changes, even though breast stroma is the major tissue compartment by volume. We have previously identified lumican and decorin as abundant small leucine-rich proteoglycans in breast stroma that show altered expression after breast tumorigenesis. In this study we have examined breast biopsies for a relationship between mammographic density and stromal alterations.. We reviewed mammograms from women aged 50-69 years who had enrolled in a provincial mammography screening program and had undergone an excision biopsy for an abnormality that was subsequently diagnosed as benign or pre-invasive breast disease. The overall mammographic density was classified into density categories. All biopsy tissue sections were reviewed and tissue blocks from excision margins distant from the diagnostic lesion were selected. Histological composition was assessed in sections stained with haematoxylin and eosin, and the expression of lumican and decorin was assessed by immunohistochemistry; both were quantified by semi-quantitative scoring.. Tissue sections corresponding to regions of high in comparison with low mammographic density showed no significant difference in the density of ductal and lobular units but showed significantly higher collagen density and extent of fibrosis. Similarly, the expression of lumican and decorin was significantly increased.. Alteration in stromal composition is correlated with increased mammographic density. Although epithelial changes define the eventual pathway for breast cancer development, mammographic density might correspond more directly to alterations in stromal composition.

Topics: Aged; Breast; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Chondroitin Sulfate Proteoglycans; Cohort Studies; Decorin; Extracellular Matrix Proteins; Female; Humans; Hyperplasia; Immunohistochemistry; Keratan Sulfate; Lumican; Mammography; Middle Aged; Precancerous Conditions; Proteoglycans; Risk Factors; Stromal Cells

Lumican mRNA has been identified as being differentially expressed between different regions of the same human breast tumor. In situ hybridization study of 26 independent breast tumors confirmed the presence of lumican mRNA in fibroblast-like cells within stroma and showed a significant increase of its expression in tumor compared to adjacent normal stroma (P < 0.001). Higher lumican expression was associated with higher tumor grade, lower estrogen receptor levels in the tumor, and younger age of the patients (P < 0.05). Reverse transcription-PCR analysis of total RNA extracted from 19 independent breast tissues exhibiting lesions that are thought to parallel tumor progression also suggests that this proteoglycan is differentially expressed during tumor progression.

Topics: Adult; Aged; Aged, 80 and over; Breast; Breast Neoplasms; Chondroitin Sulfate Proteoglycans; Electrophoresis, Polyacrylamide Gel; Female; Humans; In Situ Hybridization; Keratan Sulfate; Lumican; Middle Aged; Polymerase Chain Reaction; RNA, Messenger; Sodium Dodecyl Sulfate; Transcription, Genetic; Tumor Cells, Cultured