ITIH5 mediates epigenetic reprogramming of breast cancer cells

Extracellular matrix (ECM) is known to maintain epithelial integrity. In carcinogenesis ECM degradation triggers metastasis by controlling migration and differentiation including cancer stem cell (CSC) characteristics. The ECM-modulator inter- α-trypsin inhibitor heavy chain family member five (ITIH5) was recently identified as tumor suppressor potentially involved in impairing breast cancer progression but molecular mechanisms underlying its function are still elusive

Hormone pathway comparison in non-idiopathic and idiopathic progressive subglottic stenosis

Purpose Our previous study on the idiopathic progressive subglottic stenosis (IPSS) highlighted a possible hormonal mechanism, with over-expression of estrogen receptors alpha (ER-alpha) and progesterone receptors (PR). We tested whether such over-expression take place in non-idiopathic subglottic stenosis (NISS) as well. Methods 37 specimens of iatrogenic NISS were analyzed (20 females; mean age, 59 +/- 12 years; range 41-85). Immunoreactivity of ER-alpha and PR was calculated as the product of intensity (1 = weak, 2 = moderate, 3 = strong) and positive cells percentage (1 to 4, for 80%). This score was calculated on the stenotic tissue (ST), and stenosis margins (SM). Results The expression of PR was significantly higher in ST of IPSS compared with female and male NISS patients (8.7 +/- 3.1 vs. 4.9 +/- 3.2, p < 0.001 for IPSS vs. female and 8.7 +/- 3.1 vs. 2.1 +/- 2.7, p < 0.01 for IPSS vs. male NISS patients). Contrarily, ER-alpha showed gender differences, as both IPSS and female NISS patients had similar, yet higher ER-alpha expression compared with male NISS patients (7.0 +/- 4.2 vs. 6.5 +/- 2.5, p = NS for IPSS vs. female and 7.0 +/- 4.2 vs. 3.4 +/- 2.0, p < 0.02 for IPSS vs. male NISS patients). There was no difference in fibroblast receptor expression between ST and SM. However, ER-alpha and PR expression was significantly lower in marginal mucous glands when compared with ST. Conclusions The IPSS pathogenesis appears to be driven by hormonal mechanisms, in particular, by over-expression of PR. Marginal cells display a reduced hormone receptor density. This finding could be interpreted as a compensatory mechanism. These findings could open up for targeted IPSS treatment

Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses

Abstract Keratinocyte cancers (KC) are the most prevalent malignancies in fair‐skinned populations, posing a significant medical and economic burden to health systems. KC originate in the epidermis and mainly comprise basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Here, we combined single‐cell multi‐omics, transcriptomics, and methylomics to investigate the epigenomic dynamics during epidermal differentiation. We identified ~3,800 differentially accessible regions between undifferentiated and differentiated keratinocytes, corresponding to regulatory regions associated with key transcription factors. DNA methylation at these regions defined AK/cSCC subtypes with epidermal stem cell‐ or keratinocyte‐like features. Using cell‐type deconvolution tools and integration of bulk and single‐cell methylomes, we demonstrate that these subclasses are consistent with distinct cells‐of‐origin. Further characterization of the phenotypic traits of the subclasses and the study of additional unstratified KC entities uncovered distinct clinical features for the subclasses, linking invasive and metastatic KC cases with undifferentiated cells‐of‐origin. Our study provides a thorough characterization of the epigenomic dynamics underlying human keratinocyte differentiation and uncovers novel links between KC cells‐of‐origin and their prognosis

Lobular neoplasia and invasive lobular breast cancer: Inter-observer agreement for histological grading and subclassification

Lobular neoplasia (LN), invasive lobular breast cancer (ILBC) and related pleomorphic variants represent a distinct group of neoplastic mammary gland lesions. This study assessed the inter-observer agreement of histological grading in a series of ILBC and LN. 54 cases (36x ILBC, 18x LN) were evaluated by 17 observers. 3978 classification calls on various histological features, including nuclear grade, proliferative activity (Ki67 immunohistochemistry, categorical scoring), histological grade and pleomorphism were obtained. Pairwise Cohen’s kappa values were calculated and compared between various features and different observer subsets with variable histomorphological experience. In ILBC, pairwise inter-observer agreement for histological grade ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists compared with beginners (P < 0.001). Agreement for proliferation (Ki67) ranged from slight to almost perfect concordance and was also higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67) was superior to agreement for histological grade and nuclear grade, even among advanced and experienced histopathologists (P < 0.001). In LN, agreement for B-classification ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67 in LN) was superior to subclassification agreement based on conventional features, such as acinar distention and nuclear grade (P < 0.001). In summary, pairwise inter-observer concordance of histological grading of ILBC and LN is dependent on histomorphological experience. Assessment of proliferation by Ki67 immunohistochemistry is associated with favorable inter-observer agreement and can improve histological grading of ILBC as well as LN

The CpG island methylator phenotype in breast cancer is associated with the lobular subtype

Background: Aberrations in DNA methylation patterns are well-described in human malignancies. However, the existence of the 'CpG island methylator phenotype' (CIMP) in human breast cancer is still controversial. Materials & methods: Illumina's HumanMethylation 450K BeadChip was used to analyze genome-wide DNA methylation patterns. Chromosomal abnormalities were determined by array-based CGH. Results: Invasive lobular breast carcinomas exhibit the highest number of differentially methylated CpG sites and a strong inverse correlation of aberrant DNA hypermethylation and copy number alterations. Nine differentially methylated regions within seven genes discriminating the investigated subgroups were identified and validated in an independent validation cohort and correlated to a better relapse-free survival. Conclusion: These results depict a clear difference between genetically and epigenetically unstable breast carcinomas indicating different ways of tumor progression and/or initiation, which strongly supports the association of CIMP with the lobular subtype and provide new options for detection and therapy

Evaluation of the diagnostic performance of candidate serum biomarkers AGR3, AGR2 and their combination.

<p>Scatter plot demonstrating a highly significant elevation of (<b>A</b>) AGR3 and (<b>C</b>) AGR2 protein concentration in human serum samples from breast cancer patients (n = 40) in comparison with samples from healthy women (n = 40). ROC curve analysis for (<b>B</b>) AGR3, (<b>D</b>) AGR2 and (<b>E</b>) the combination of both proteins. ** <i>P</i> < 0.01, *** <i>P</i> < 0.001. ROC: receiver operating characteristic, AUC: area under the curve, 95% CI: 95% confidence interval.</p

Univariate analysis of clinico-pathological parameters influencing tumour-specific survival in the group of grade^a 1 and 2 breast tumours.

<p>^aAccording to Bloom and Richardson, as modified by Elston and Ellis [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122106#pone.0122106.ref032" target="_blank">32</a>].</p><p>^bLog-rank test at the two-sided significance level of 0.05.</p><p>^cMedian immunoreactive score (IRS) according to Remmele and Stegner [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122106#pone.0122106.ref030" target="_blank">30</a>] was used as cut-off: AGR3 low (IRS 0–4), AGR3 high (IRS 6–12).</p><p>^dAccording to TNM classification by Sobin and Wittekind [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122106#pone.0122106.ref058" target="_blank">58</a>].</p><p>^eImmunoreactive score (IRS) according to Remmele and Stegner [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122106#pone.0122106.ref030" target="_blank">30</a>].</p><p>^fOverexpression of the <i>ERBB2</i> gene (Her-2/neu) was diagnosed analogously to the threshold of the DAKO-Score system based on IHC assay. Significant P-values are marked in bold face.</p><p>Univariate analysis of clinico-pathological parameters influencing tumour-specific survival in the group of grade<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122106#t001fn001" target="_blank">^a</a> 1 and 2 breast tumours.</p