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The analysis of FFPE tissue sections stained with haematoxylin and eosin (H&E) or immunohistochemistry (IHC) is essential for the pathologic assessment of surgically resected breast cancer specimens. IHC staining has been broadly adopted into diagnostic guidelines and routine workflows to assess the status of several established biomarkers, including ER, PGR, HER2 and KI67. Biomarker assessment can also be facilitated by computational pathology image analysis methods, which have made numerous substantial advances recently, often based on publicly available whole slide image (WSI) data sets. However, the field is still considerably limited by the sparsity of public data sets. In particular, there are no large, high quality publicly available data sets with WSIs of matching IHC and H&E-stained tissue sections from the same tumour. Here, we publish the currently largest publicly available data set of WSIs of tissue sections from surgical resection specimens from female primary breast cancer patients with matched WSIs of corresponding H&E and IHC-stained tissue, consisting of 4,212 WSIs from 1,153 patients. [ABSTRACT FROM AUTHOR]

Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC.Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry.Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours.Conclusions: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC. [ABSTRACT FROM AUTHOR]

To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed. Here we report high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). Each sample group shows a distinct protein profile. By integrative analysis we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. Instead, we uncover previously unrecognized molecular and pathway events, for example, several miRNA target correlations present at protein but not at mRNA level. Notably, we identify two metabolic shifts in the citric acid cycle (TCA cycle) during prostate cancer development and progression. Our proteogenomic analysis uncovers robustness against genomic and transcriptomic aberrations during prostate cancer progression, and significantly extends understanding of prostate cancer disease mechanisms. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor controls cell growth and survival through transcriptional regulation of gene expression. Previously, we found that the human telomerase reverse transcriptase (hTERT) gene is downregulated by p53. To investigate if hTERT downregulation has a role in p53-dependent apoptosis, we tested if constitutive expression of telomerase could inhibit p53-induced apoptosis. Here we show that constitutive hTERT expression results in increased survival following activation of exogenous temperature-sensitive p53 in BL41 Burkitt lymphoma cells. Similarly, constitutive hTERT expression inhibited wild-type p53-dependent apoptosis in response to mitomycin C or 5-fluorouracil in HCT116 colon carcinoma cells carrying endogenous p53. A telomerase-inactive hTERT mutant was equally efficient in antagonizing p53-induced apoptosis. These findings support the notion that hTERT has antiapoptotic activity and demonstrate that p53-mediated downregulation of hTERT is critical for efficient p53-dependent apoptosis.Oncogene (2005) 24, 1320-1327. doi:10.1038/sj.onc.1208232 Published online 20 December 2004 [ABSTRACT FROM AUTHOR]

We address here the effects of increasing fluencies of UV-radiation on stability, modifications, activity and HDM2-interactions of endogenous p53 tumor suppressor and on cellular damage response of human diploid fibroblasts. Low amounts of UVB/C-radiation induced a transient cell cycle arrest of the cells which correlated with rapid but transient increase in p53 levels. In contrast, high UV-fluency caused cell apoptosis and a slower but sustained increase in p53. Regulation of p53 target genes was highly dependent on the radiation dose used. Whereas low doses induced p21/Cip1/Waf1 and HDM2, high doses induced only GADD45 and BAX increasing the BAX:BCL-2 ratio. The levels of HDM2, a negative regulator of p53, increased only by the low dose of UVC and p53-HDM2 association was promoted. In the absence of HDM2-induction after the high dose of UV-radiation p53-HDM2-interaction was promoted, but HDM2 failed to downregulate p53. p53 site-specific modifications (Ser15, Ser33, Ser37, Lys382) varied kinetically and were dependent on the fluency of the radiation used. Maximal phosphorylation of p53 on Ser15 and Ser33 correlated with increased levels of HDM2-free p53. The results suggest that regulation of p53 and HDM2 by UV-radiation is highly dose-dependent and contributes to the outcome of the cellular response. Oncogene (2001) 20, 6784–6793. [ABSTRACT FROM AUTHOR]

Cancer involves histological changes in tissue, which is of primary importance in pathological diagnosis and research. Automated histological analysis requires ability to computationally separate pathological alterations from normal tissue with all its variables. On the other hand, understanding connections between genetic alterations and histological attributes requires development of enhanced analysis methods suitable also for small sample sizes. Here, we set out to develop computational methods for early detection and distinction of prostate cancer-related pathological alterations. We use analysis of features from HE stained histological images of normal mouse prostate epithelium, distinguishing the descriptors for variability between ventral, lateral, and dorsal lobes. In addition, we use two common prostate cancer models, Hi-Myc and Pten+/− mice, to build a feature-based machine learning model separating the early pathological lesions provoked by these genetic alterations. This work offers a set of computational methods for separation of early neoplastic lesions in the prostates of model mice, and provides proof-of-principle for linking specific tumor genotypes to quantitative histological characteristics. The results obtained show that separation between different spatial locations within the organ, as well as classification between histologies linked to different genetic backgrounds, can be performed with very high specificity and sensitivity. [ABSTRACT FROM AUTHOR]