Breast carcinomas are often infiltrated by inflammatory cells, particularly macrophages and T lymphocytes, but the significance of these cells remains unclear. One possible role of these inflammatory ...cells is that they represent a cell-mediated immune response against the carcinoma. CD8(+) lymphocytes are a known crucial component of cell-mediated immunity. The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+) cytotoxic lymphocytes in breast cancer. Tumor-infiltrating CD8(+) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up. The number of CD8(+) T cells was counted in tumor nests (intratumoral), in stroma adjacent to tumor cells, and in stroma distant to tumor cells, and their relationship with clinical outcome was determined. The total number of CD8(+) cells was positively correlated with tumor grade (r(s) = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor-alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001). The total patient cohort was randomly divided into two separate training and validation sets before performing univariate survival analysis. Total number and distant stromal CD8(+) lymphocytes were associated with better patient survival (P = .041 and P < .001, respectively) in the training set. In multivariate analysis, total CD8(+) T-cell count was an independent prognostic factor in both training and validation sets. These results suggest that tumor-infiltrating CD8(+) T lymphocytes have antitumor activity as judged by their favorable effect on patients' survival and could potentially be exploited in the treatment of breast cancer.
Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients ...with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype.
We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin CK5/6 or epidermal growth factor receptor EGFR) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy.
The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term ...follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis
. It is therefore essential to identify patients who have a high risk of late relapse
. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns
; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression
). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
The role of glutaminase in cancer Masisi, Brendah K; El Ansari, Rokaya; Alfarsi, Lutfi ...
Histopathology,
March 2020, Letnik:
76, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer and is recognised as a key metabolic change in cancer cells. Breast cancer is a heterogeneous disease with different ...morphological and molecular subtypes and responses to therapy, and breast cancer cells are known to rewire glutamine metabolism to support survival and proliferation. Glutaminase isoenzymes (GLS and GLS2) are key enzymes for glutamine metabolism. Interestingly, GLS and GLS2 have contrasting functions in tumorigenesis. In this review, we explore the role of glutaminase in cancer, primarily focusing on breast cancer, address the role played by oncogenes and tumour suppressor genes in regulating glutaminase, and discuss current therapeutic approaches to targeting glutaminase.
Angiosperms show a remarkable range in genome size (GS), yet most species have small genomes, despite the frequency of polyploidy and repeat amplification in the ancestries of most lineages. It has ...been suggested that larger genomes incur costs that have driven selection for GS reduction, although the nature of these costs and how they might impact selection remain unclear. We explore potential costs of increased GS encompassing impacts on minimum cell size with consequences for photosynthesis and water-use efficiency and effects of greater nitrogen and phosphorus demands of the nucleus leading to more severe trade-offs with photosynthesis. We suggest that nutrient-, water-, and/or CO2-stressed conditions might favour species with smaller genomes, with implications for species’ ecological and evolutionary dynamics.
There has been much recent interest in the role of GS in influencing plant growth and fitness, with evidence suggesting it influences where and how plants grow.We evaluate the evidence revealing interactions between GS, photosynthesis, water-use efficiency, and environmental conditions (CO2, water, and nutrients) on plant growth.The evidence suggests that GS–environmental interactions have provided ecological selection pressures on plants, impacting plant communities, and may have generated evolutionary selection on plants, leading to genome downsizing.We propose that GS is an essential variable that needs to be considered when predicting the response of plants, in both natural and agricultural ecosystems, so we can best predict the effects of global eutrophication and climate change.
We recently reported that the mRNA-based, 21-gene Genomic Health recurrence score (GHI-RS) provided additional prognostic information regarding distant recurrence beyond that obtained from classical ...clinicopathologic factors (age, nodal status, tumor size, grade, endocrine treatment) in women with early breast cancer, confirming earlier reports. The aim of this article is to determine how much of this information is contained in standard immunohistochemical (IHC) markers.
The primary cohort comprised 1,125 estrogen receptor-positive (ER-positive) patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial who did not receive adjuvant chemotherapy, had the GHI-RS computed, and had adequate tissue for the four IHC measurements: ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67. Distant recurrence was the primary end point, and proportional hazards models were used with sample splitting to control for overfitting. A prognostic model that used classical variables and the four IHC markers (IHC4 score) was created and assessed in a separate cohort of 786 patients.
All four IHC markers provided independent prognostic information in the presence of classical variables. In sample-splitting analyses, the information in the IHC4 score was found to be similar to that in the GHI-RS, and little additional prognostic value was seen in the combined use of both scores. The prognostic value of the IHC4 score was further validated in the second separate cohort.
This study suggests that the amount of prognostic information contained in four widely performed IHC assays is similar to that in the GHI-RS. Additional studies are needed to determine the general applicability of the IHC4 score.
MicroRNAs (miRNAs), a class of short non-coding RNAs found in many plants and animals, often act post-transcriptionally to inhibit gene expression.
Here we report the analysis of miRNA expression in ...93 primary human breast tumors, using a bead-based flow cytometric miRNA expression profiling method. Of 309 human miRNAs assayed, we identify 133 miRNAs expressed in human breast and breast tumors. We used mRNA expression profiling to classify the breast tumors as luminal A, luminal B, basal-like, HER2+ and normal-like. A number of miRNAs are differentially expressed between these molecular tumor subtypes and individual miRNAs are associated with clinicopathological factors. Furthermore, we find that miRNAs could classify basal versus luminal tumor subtypes in an independent data set. In some cases, changes in miRNA expression correlate with genomic loss or gain; in others, changes in miRNA expression are likely due to changes in primary transcription and or miRNA biogenesis. Finally, the expression of DICER1 and AGO2 is correlated with tumor subtype and may explain some of the changes in miRNA expression observed.
This study represents the first integrated analysis of miRNA expression, mRNA expression and genomic changes in human breast cancer and may serve as a basis for functional studies of the role of miRNAs in the etiology of breast cancer. Furthermore, we demonstrate that bead-based flow cytometric miRNA expression profiling might be a suitable platform to classify breast cancer into prognostic molecular subtypes.
Purpose
MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. ...This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC).
Methods
MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of
MMP9
expression. GSEA gene enrichment analyses were used to evaluate
MMP9
associated pathways.
Results
MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts,
MMP9
expression was also associated with poor patients’ outcome. Transcriptomic analysis confirmed a positive association between
MMP9
and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways.
Conclusion
This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted.
Breast cancer (BC) is a heterogeneous disease characterised by variant biology and patient outcome. The amino acid transporter, SLC7A5, plays a role in BC although its impact on patient outcome in ...different BC subtypes remains to be validated. This study aimed to determine whether the clinicopathological and prognostic value of SLC7A5 is different within the molecular classes of BC.
SLC7A5 was assessed at the genomic level, using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data (n = 1980), and proteomic level, using immunohistochemical analysis and tissue microarray (TMA) (n = 2664; 1110 training and 1554 validation sets) in well-characterised primary BC cohorts. SLC7A5 expression correlated with clinicopathological and biological parameters, molecular subtypes and patient outcome.
SLC7A5 mRNA and protein expression were strongly correlated with larger tumour size and higher grade. High expression was observed in triple negative (TN), human epidermal growth factor receptor 2 (HER2)+, and luminal B subtypes. SLC7A5 mRNA and protein expression was significantly associated with the expression of the key regulator of tumour cell metabolism, c-MYC, specifically in luminal B tumours only (p = 0.001). High expression of SLC7A5 mRNA and protein was associated with poor patient outcome (p < 0.001) but only in the highly proliferative oestrogen receptor (ER)+/ luminal B (p = 0.007) and HER2+ classes of BC (p = 0.03). In multivariate analysis, SLC7A5 protein was an independent risk factor for shorter breast-cancer-specific survival only in ER+ high-proliferation tumours (p = 0.02).
SLC7A5 appears to play a role in the aggressive highly proliferative ER+ subtype driven by MYC and could act as a potential therapeutic target. Functional assessment is necessary to reveal the specific role played by this transporter in the ER+ highly proliferative subclass and HER2+ subclass of BC.
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