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Identification of long non‑coding RNA‑mediated transcriptional dysregulation triplets reveals global patterns and prognostic biomarkers for ER+/PR+, HER2‑ and triple negative breast cancer.

ABSTRACT: Breast cancer (BRCA) is the most common type of cancer in adult females. Estrogen receptor (ER)+/progesterone receptor (PR)+, human epidermal‑growth factor receptor 2 (HER2)‑ BRCA and triple‑negative breast cancer (TNBC) are two important subtypes of this disease. Long non‑coding RNA (lncRNA)‑mediated transcriptional dysregulation triplets (lncTDTs) may contribute to the development of cancer; however, the precise functional roles of lncTDTs in ER+/PR+, HER2‑ BRCA and TNBC require further investigation. In the present study, an integrated and computational approach was conducted to identify lncTDTs based on transcription factor (TF), gene, lncRNA expression profiles and experimentally verified TF‑gene interactions. The regulatory patterns of these lncTDTs are complex and differed in ER+/PR+, HER2‑ BRCA and TNBC. Of note, five common lncTDTs were reported for these BRCA subtypes. Functional analysis revealed lncTDTs to be enriched in the PI3K/AKT signaling pathway within the two BRCA subtypes. Additionally, certain lncTDTs were associated with survival and may be considered candidate prognostic biomarkers for BRCA subtypes. Collectively, the results of the present study provide novel insight into the functions and mechanisms of lncRNAs in ER+/PR+, HER2‑ BRCA and TNBC, and may aid the development of targeted treatments against certain subtypes of BRCA.

SUBMITTER: Du Z

PROVIDER: S-EPMC6657959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Progression in digital pathology has yielded new opportunities for a remote work environment. We evaluated the utility of digital review of breast cancer immunohistochemical prognostic markers (IHC) using whole slide images (WSI) from formalin fixed paraffin embedded (FFPE) cytology cell block specimens (CB) using three different scanners.CB from 20 patients with breast cancer diagnosis and available IHC were included. Glass slides including 20 Hematoxylin and eosin (H&E), 20 Estrogen Receptor (ER), 20 Progesterone Receptor (PR), 16 Androgen Receptor (AR), and 20 Human Epidermal Growth Factor Receptor 2 (HER2) were scanned on 3 different scanners. Four breast pathologists reviewed the WSI and recorded their semi-quantitative scoring for each marker. Kappa concordance was defined as complete agreement between glass/digital pairs. Discordances between microscopic and digital reads were classified as a major when a clinically relevant change was seen. Minor discordances were defined as differences in scoring percentages/staining pattern that would not have resulted in a clinical implication. Scanner precision was tabulated according to the success rate of each scan on all three scanners.In total, we had 228 paired glass/digital IHC reads on all 3 scanners. There was strong concordance kappa ≥0.85 for all pathologists when comparing paired microscopic/digital reads. Strong concordance (kappa ≥0.86) was also seen when comparing reads between scanners.Twenty-three percent of the WSI required rescanning due to barcode detection failures, 14% due to tissue detection failures, and 2% due to focus issues. Scanner 1 had the best average precision of 92%. HER2 IHC had the lowest intra-scanner precision (64%) among all stains.This study is the first to address the utility of WSI in breast cancer IHC in CB and to validate its reporting using 3 different scanners. Digital images are reliable for breast IHC assessment in CB and offer similar reproducibility to microscope reads.

Project description:Background: Extensive amounts of archived formalin fixed paraffin embedded (FFPE) human tumor tissues are the ultimate resource to investigate signaling network underlying tumorigenesis in human. Yet, their usage is severely limited for lacking of suitable protein techniques. In this study, a quantitative, objective, absolute, and high throughput immunoblot method, quantitative dot blot (QDB), was explored to address this issue by investigating the putative relationship between estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2) pathways in breast cancer tumorigenesis. Methods: In this descriptive observational retrospective study, ER, PR, Her2, and Ki67 protein levels were measured absolutely and quantitatively in 852 FFPE breast cancer tissues using the QDB method. ER, PR, and Her2 levels were charted on the X, Y, and Z-axes to observe samples distribution in a 3D scatterplot. Results: A "seesaw" relationship between ER/PR and Her2 pathways was observed in ER-PR-Her2 space, characterized by the expression levels of these 3 proteins. Specimens with strong expressions of ER/PR proteins were found spreading along the ER/PR floor while those with strong Her2 expression were found wrapping around the Her2 axis. Those lacking strong expressions of all 3 proteins were found accumulating at the intersection of the ER, PR, and Her2 axes. Few specimens floated in the ER-PR-Her2 space to suggest the lack of co-expression of all 3 proteins simultaneously. Ki67 levels were found to be significantly reduced in specimens spreading in the ER-PR space. Conclusions: The unique distribution of specimens in ER-PR-Her2 space prior to any clinical intervention provided visual support of bidirectional talk between ER/PR and Her2 pathways in breast cancer specimens. Clinical interventions to suppress these 2 pathways alternatively warrant further exploration for breast cancer patients accordingly. Our study also demonstrated that the QDB method is an effective tool to analyze archived FFPE cancer specimens in biomedical research.

Project description:BackgroundImmune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions (ifCa2+), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER-/PR-/HER2+ breast cancer cells.MethodsHuman primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET.ResultsMET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, ifCa2+, IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, ifCa2+, and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures.ConclusionsOur results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and ifCa2+, and increased cell necrosis during breast cancer cells-MOs crosstalk.

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Identification of long non‑coding RNA‑mediated transcriptional dysregulation triplets reveals global patterns and prognostic biomarkers for ER+/PR+, HER2‑ and triple negative breast cancer.

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