Breast cancer stem cells: Features, key drivers and treatment options

Dittmer, Jürgen

doi:10.1016/j.semcancer.2018.07.007

Cited by 135 publications

(96 citation statements)

References 297 publications

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“…Thus, it is fairly important and urgent to identify the key genes driving the crucial cellular processes involved in the transformation from quiescent stem cells to non-renewing cancer cells with unlimited proliferative potential. In the present study, we first analysed the correlation between mRNAsi scores and clinical characteristics in BRCA samples and proved that tumour tissues always had higher stemness than normal tissues, which was consistent with previous findings [16]. Considering that the tumour tissues were composed of complex cell types, including cancerrelated cells and normal microenvironment cells, and mRNAsi was a stemness index for all cells in a certain sample, to eliminate the bias of mRNAsi caused by noncancer cells in tumour samples, we calculated corrected mRNAsi scores using the tumour purity.…”

Section: Discussionsupporting

confidence: 90%

Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis

Pei

Wang

2020

J Transl Med

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Background: With the gradual unveiling of tumour heterogeneity, cancer stem cells (CSCs) are now being considered the initial component of tumour initiation. However, the mechanisms of the growth and maintenance of breast cancer (BRCA) stem cells are still unknown. Methods:To explore the crucial genes modulating BRCA stemness characteristics, we combined the gene expression value and mRNA expression-based stemness index (mRNAsi) of samples from The Cancer Genome Atlas (TCGA), and the mRNAsi was corrected using the tumour purity (corrected mRNAsi). mRNAsi and corrected mRNAsi were analysed and showed a close relationship with BRCA clinical characteristics, including tumour depth, pathological staging and survival status. Next, weighted gene co-expression network analysis (WGCNA) was applied to distinguish crucial gene modules and key genes. A series of functional analyses and expression validation of key genes were conducted using multiple databases, including Oncomine, Gene Expression Omnibus (GEO) and Gene Expression Profiling Integrative Analysis (GEPIA). Results:This study found that mRNAsi and corrected mRNAsi scores were higher in BRCA tissues than that in normal tissues, and both of them increased with tumour stage. Higher corrected mRNAsi scores showed worse overall survival outcomes. We screened 3 modules and 32 key genes, and those key genes were found to be strongly correlated with each other. Functional analysis revealed that the key genes were related to cell fate decision events such as the cell cycle, cellular senescence, chromosome segregation and mitotic nuclear division. Among 32 key genes, we identified 12 genes that strongly correlated with BRCA survival. Conclusions:Thirty-two genes were found to be closely related to BRCA stem cell characteristics; among them, 12 genes showed prognosis-oriented effects in BRCA patients. The most significant signalling pathway related to stemness in BRCA was the cell cycle pathway, which may support new ideas for screening therapeutic targets to inhibit BRCA stem characteristics. These findings may highlight some therapeutic targets for inhibiting BRCA stem cells. BackgroundBreast cancer is one of the most common and lethal cancers in women. According to the latest cancer statistics, the number of estimated new cases and deaths from breast cancer was 268,600 and 41,760, respectively, and the incidence and mortality rates of breast cancer were nearly 30% and 15%, respectively, among all cancers in

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Section: Discussionsupporting

confidence: 90%

Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis

Pei

Wang

2020

J Transl Med

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“…Both pathways are typically active in stem cells, suggesting that multiple small clones may be present and spread throughout the PT and composed of cancer stem cells. This fits well with the cancer stem cell hypothesis, which assumes that small groups of relatively quiescent cancer cells that have acquired stem cell characteristics are present in tumor tissue (1,38,39). Both pathways are generally thought to play an important role in governing metastatic behavior and therapy resistance of cancer stem cells, another hallmark of cancer (1).…”

Section: Within Tumor Heterogeneity Of Signaling Pathway Activitysupporting

confidence: 76%

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Inda

Swinderen

Brussel

et al. 2020

Preprint

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BackgroundTargeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated.MethodsActivity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFβ, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four “quadrant” samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A “checkerboard” model was introduced to explain the observed heterogeneity in PT.ResultsWithin PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFβ pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway.ConclusionWith a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFβ and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

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“…Previous studies showed that BC is a stem cell disease and phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT)-mammalian targets of rapamycin (mTOR) signaling is one important pathway for BC development. 31,32 Hence, the effect of baicalin on stem cell function and potential signaling pathway should be explored in future. Moreover, the poor bioavailability limited the application of baicalin in clinical.…”

Section: Dovepressmentioning

confidence: 99%

<p>Baicalin Inhibits Cell Viability, Migration and Invasion in Breast Cancer by Regulating miR-338-3p and MORC4</p>

Duan

Guo

Pei

et al. 2019

OTT

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Background: Baicalin is a natural compound from the roots of Scutellaria lateriflora Georgi, which plays anti-cancer role in multiple cancers. However, the exact role and potential underlying mechanism of baicalin in breast cancer (BC) remain poorly understood. Methods: Thirty BC patients were recruited in this study. MCF-10A, MCF-7 and MDA-MB-231 cells were used to investigate the anti-cancer role of baicalin in vitro. Cell viability, migration, invasion and apoptosis were measured by MTT, trans-well and flow cytometry, respectively. The expression levels of microRNA-338-3p (miR-338-3p) and microrchidia family CW-type zincfinger 4 (MORC4) were measured by quantitative real-time polymerase chain reaction or Western blot. The interaction between miR-338-3p and MORC4 was explored by luciferase reporter assay and RNA immunoprecipitation. Results: We found that Baicalin treatment inhibited cell viability, migration and invasion but promoted apoptosis of BC cells. The expression of miR-338-3p was decreased in BC tissues and cells and miR-338-3p overexpression suppressed cell viability, migration and invasion but induced apoptosis. MiR-338-3p expression was reversed by baicalin exposure and inhibition of miR-338-3p attenuated the role of baicalin in viability, apoptosis, migration and invasion. MORC4 mRNA level was increased in BC tissues and cells, which was decreased by baicalin exposure. MORC4 was a target of miR-338-3p and its overexpression alleviated the effect of miR-338-3p on cell viability, apoptosis, migration and invasion. Conclusion: In conclusion, baicalin suppressed cell viability, migration and invasion but promoted apoptosis in BC cells by regulating miR-338-3p and MORC4, indicating the promising pharmacological value of baicalin in BC treatment.

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Breast cancer stem cells: Features, key drivers and treatment options

Cited by 135 publications

References 297 publications

Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis

Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

<p>Baicalin Inhibits Cell Viability, Migration and Invasion in Breast Cancer by Regulating miR-338-3p and MORC4</p>

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