Contribution of Stemness-linked Transcription Regulators to the Progression of Breast Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
David Segura-Bautista ◽  
Guadalupe Maya-Nunez ◽  
Arturo Aguilar-Rojas ◽  
Maira Huerta-Reyes ◽  
Marco Allan Pérez-Solis
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Immunological Response ◽  
Malignant Cells ◽  
Mesenchymal Transition ◽  
Underlying Causes ◽  
Transcription Regulators ◽  
Therapeutic Perspective

: Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial-Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.

Classifying circulating, mutation bearing tumor cells from breast cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 580-580
Author(s):  
William Strauss ◽  
Paul W. Dempsey ◽  
Jessamine Winer-Jones ◽  
Catherine Bingham ◽  
R. Katherine Alpaugh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Molecular Analysis ◽  
New Technologies ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Patients ◽  
Disease Heterogeneity ◽  
Mesenchymal Transition ◽  
Tissue Biopsy

580 Background: The treatment of advanced breast cancer demands systemic therapies that can address disease heterogeneity and the development of treatment resistance without a “real-time” molecular window into disease biology. New technologies have focused on increased capture and molecular analysis of circulating tumor cells (CTCs) including cells undergoing epithelial mesenchymal transition (EMT). We conducted a pilot experiment to test the efficiency of capture and cytokeratin (CK) detection and the presence of single point variants (SNV) to determine the best utility of scoring alternatives for CTC. Methods: EpCAM expressing CTC were recovered from breast cancer patients using CellSearch (Veridex) and LiquidBiopsy (Cynvenio Biosystems). EpCAM recovery and CK scoring were indexed in spiked samples and in 12 inflammatory breast cancer (IBC) patient samples using antibodies against CKs 7, 8 or CKs 1-8, 10, 13-16, 18, 19. Additionally, LiquidBiopsy template was analyzed using an Ampliseq 1.0 panel on the IonTorrent PGM. SNV present in the CTC but not white blood cell (WBC) negative controls were identified and where possible, compared to tissue biopsy SNV analyzed using Foundation One (Foundation Medicine). Results: CTCs were detected using CellSearch 10/12 (83%) (range 0-2502 CTC/7.5ml) and LiquidBiopsy 12/12 (100%) (range 6-2800 CTC/7.5mL). More CK positive events were scored using CKs 1-8, 10, 13-16, 18, 19 than CKs 7, 8 in patient samples. Upon sequencing, shared germline polymorphisms were observed in CTC and WBC. Conversely, 1 or 2 SNV were detected in the Epcam selected population but not WBC controls from 6/12 patients (frequency 1.1%-2.1% with 520-5160x coverage) with SNV observed in TP53, MPL, PIK3ca, MET and IDH1. All but one of the PIK3ca mutations were absent in evaluable tissue biopsy. Conclusions: CTC recovery and scoring are two separate events. Altered CK detection emphasized the need to tailor CTC classification to specific disease settings. Sequence analysis showed one correlated SNV among 6 evaluable comparisons to tissue reflecting variable analysis as well as the biologic disparity of metastatic disease. This pilot demonstrates the feasibility of using CTC for molecular analysis.

Evaluation of risk recurrence in early breast cancer assessed by Oncotype DX and tumor cell dissemination to blood and bone marrow.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11516-e11516
Author(s):  
Bahriye Aktas ◽  
Agnes Bankfalvi ◽  
Martin Leonhard Heubner ◽  
Rainer Kimmig ◽  
Sabine Kasimir-Bauer
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Statistical Analysis ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Data Set ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Genomic Test

e11516 Background: The OncotypeDX assay is a validated genomic test that predicts the likelihood of breast cancer (BC) recurrence, patients’ (pts) survival within 10 years of diagnosis and benefit of chemotherapy in early-stage, N0, ER-pos BC. In addition, disseminated tumor cells (DTC) in the bone marrow (BM) and circulating tumor cells (CTCs) in blood, especially stemness like tumor cells (slCTCs) including cells being able to perform epithelial-mesenchymal transition (EMT), have been associated with worse outcome in BC. Here we use OncotypeDX as well as the presence of DTCs, CTCs and slCTCs to evaluate the risk for recurrence in early BC pts. Methods: In total, 90 pts with newly diagnosed HER2-neg early stage BC received breast conserving surgery and sentinel lymphonodectomy. 17 pts were ER-/PR-, 12 pts ER+/PR-, 3 pts ER-/PR+ and 59 pts were ER+/PR+. Analysis of OncotypeDX and KI67 were performed. In case of G2 tumors, UPA and PAI1 were determined as further proliferation markers in tissue samples. Two BM aspirates from these patients were analyzed by immunocytochemistry for DTCs using the pan-cytokeratin antibody A45-B/B3. Furthermore, 2 x5 ml blood were analyzed for CTCs with the AdnaTest BreastCancer for the detection of EpCAM, MUC-1, HER-2, and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for the presence of slCTCs using the AdnaTest EMT (multiplex RT-PCR for TWIST, AKT2, PI3K), and the AdnaTest TumorStemCell (ALDH1). Results: OncotypeDX was performed in 68/91 cases. 30/68 pts (44%) had a low RS, 29/68 pts (43%) an intermediate RS and 9/68 pts (13%) a high RS, respectively. BM aspiration could be performed in 70/91 pts with a positivity rate of 34% (24/70) for DTCs. CTCs were detected in 16/68 (25%) evaluable pts and slCTCs in 27/62 (44%) pts, respectively. In preliminary statistical analysis, KI67, PR and grading are showing association to RS as well as the presence of slCTCs. Tissue samples of patients with G2 tumors (N=65) underwent evaluation for UPA/PAI1analysis. Conclusions: Final statistical analysis for the complete data set including correlations to RS with all evaluable parameter will be available for presentation at the ASCO.

scholarly journals Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Samane Khoshbakht ◽  
Sadegh Azimzadeh Jamalkandi ◽  
Ali Masudi-Nejad
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Rank Test ◽  
Support Vector ◽  
Mesenchymal Transition ◽  
Menstrual Cycles

Abstract Background Circulating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways and their metastasis driver genes which promote survival of CTCs is not well introduced using network approaches. Methods Here, to investigate the unknown pathways of single/cluster CTCs, the co-expression network was reconstructed, using WGCNA (Weighted Correlation Network Analysis) method. Having used the hierarchical clustering, we detected the Immune-response and EMT subnetworks. The metastatic potential of genes was assessed and validated through the support vector machine (SVM), neural network, and decision tree methods on two external datasets. To identify the active signaling pathways in CTCs, we reconstructed a casual network. The Log-Rank test and Kaplan–Meier curve were applied to detect prognostic gene signatures for distant metastasis-free survival (DMFS). Finally, a predictive model was developed for metastasis risk of patients using VIF-stepwise feature selection. Results Our results showed the crosstalk among EMT, the immune system, menstrual cycles, and the stemness pathway in CTCs. In which, fluctuation of menstrual cycles is a new detected pathway in breast cancer CTCs. The reciprocal association between immune responses and EMT was identified in CTCs. The SVM model indicated a high metastatic potential of EMT subnetwork (accuracy, sensitivity, and specificity scores were 87%). The DMFS model was identified to predict patients’ metastasis risks. (c-index = 0.7). Finally, novel metastatic biomarkers of KRT18 and KRT19 were detected in breast cancer CTCs. Conclusions In conclusion, the reciprocal interplay among critical unknown pathways in CTCs manifests both their survival in blood and metastatic potentials. Such findings may help to develop more precise predictive metastatic-risk models or detect pivotal metastatic biomarkers.

scholarly journals Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2780 ◽  
Author(s):  
Olga E. Savelieva ◽  
Liubov A. Tashireva ◽  
Evgeniya V. Kaigorodova ◽  
Angelina V. Buzenkova ◽  
Rustam Kh. Mukhamedzhanov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Receptor Expression ◽  
Stem Cell Markers ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Tumor Cell Heterogeneity ◽  
Stromal Cell Derived Factor

The presence of stem and epithelial–mesenchymal-transition (EMT) features in circulating tumor cells (CTCs) determines their invasiveness, adaptability to the microenvironment, and resistance to proapoptotic signals and chemotherapy. It also allows them to fulfil the role of metastatic “seeds”. We evaluated the heterogeneity of stem CTCs by their CD44, ALDH1, and CD133 expression depending on N-cadherin expression in breast-cancer patients. A total of 38 female patients were selected for this study. CTC phenotypes were determined by flow cytometry before any type of treatment. Multiplex immunofluorescence was used for the evaluation of tumor-cell heterogeneity in primary lesions. In patients who had CD44-CD24- CTCs, a subset of cells with the expression of other stem-cell markers (CD133 and ALDH1) were detected. Expression of CD133 and/or ALDH1 may be associated with expression of N-cadherin: all populations of N-cadherin+ CTCs demonstrate stem features; in the absence of N-cadherin expression, true nonstem (CD44-CD24-CD133-ALDH1-) cells are found. The heterogeneity of stem marker expression in CTCs was observed regardless of N-cadherin expression. In our study, stromal cell-derived factor-1 (SDF-1) receptor expression in CTCs did not depend on stemlike traits, but was instead associated with N-cadherin expression. Subpopulations of tumor cells, detected both in tumors and blood, were identified. Breast cancer was characterized by pronounced interpersonal and intrapersonal heterogeneity of CTCs by the presence and combination of various stem features and N-cadherin expression. To complete the characterization of stemlike features of CTCs, we suggest the simultaneous use of the three stem markers.

scholarly journals Expression of Stem Cell and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells of Breast Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Natalia Krawczyk ◽  
Franziska Meier-Stiegen ◽  
Malgorzata Banys ◽  
Hans Neubauer ◽  
Eugen Ruckhaeberle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Current Data ◽  
Stem Cell Markers ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Evaluation and characterization of circulating tumor cells (CTCs) have become a major focus of translational cancer research. Presence of CTCs predicts worse clinical outcome in early and metastatic breast cancer. Whether all cells from the primary tumor have potential to disseminate and form subsequent metastasis remains unclear. As part of the metastatic cascade, tumor cells lose their cell-to-cell adhesion and undergo epithelial-mesenchymal transition (EMT) in order to enter blood circulation. During EMT epithelial antigens are downregulated; thus, such tumor cells might elude classical epithelial marker-based detection. Several researchers postulated that some CTCs express stem cell-like phenotype; this might lead to chemoresistance and enhanced metastatic potential of such cells. In the present review, we discuss current data on EMT and stem cell markers in CTCs of breast cancer and their clinical significance.

scholarly journals Epigenetic Silencing of HER2 Expression during Epithelial-Mesenchymal Transition Leads to Trastuzumab Resistance in Breast Cancer

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 868
Author(s):  
Babak Nami ◽  
Avrin Ghanaeian ◽  
Corbin Black ◽  
Zhixiang Wang
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Silencing ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Mesenchymal Transition ◽  
Erbb2 Gene ◽  
Positive Breast Cancer

HER2 receptor tyrosine kinase (encoded by the ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (HER2-positive breast cancers). Resistance to HER2-targeting therapies is partially due to the loss of HER2 expression in tumor cells during treatment. However, little is known about the exact mechanism of HER2 downregulation in HER2-positive tumor cells. Here, by analyzing publicly available genomic data we investigate the hypothesis that epithelial-mesenchymal transition (EMT) abrogates HER2 expression by epigenetic silencing of the ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. As result, HER2 expression was found to be positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes, respectively. The ERBB2 chromatin of HER2-high epithelial-like breast cancer cells and HER2-low mesenchymal-like cells were found to be open/active and closed/inactive, respectively. Decreased HER2 expression was correlated with increased EMT phenotype, inactivated chromatin and lower response to lapatinib. We also found that induction of EMT in the HER2-positive breast cancer cell line BT474 resulted in downregulated HER2 expression and reduced trastuzumab binding. Our results suggest that ERBB2 gene silencing by epigenetic regulation during EMT may be a mechanism of de novo resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.

Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT

2021 ◽  
Author(s):  
Yihui Zhu ◽  
Zhonghua Tao ◽  
Ying Chen ◽  
Shuchen Lin ◽  
Mingyu Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Distant Metastasis ◽  
Intercellular Communication ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Biologically Active ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Purpose Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high risk of distant metastasis, in which the intercellular communication between tumor cells also plays a role. Exosomes can be released by tumor cells and promote distant metastasis through intercellular communication or changes in tumor microenvironment, it is an optimized transportation facility for biologically active payloads. This was a hypothesis-generating research on role of exosomal payload in TNBC distant metastasis. Methods Exosomes isolated from supernatant of MDA-MB-231 and MDA-MB-231-HM (a highly pulmonary metastatic variant of parental MDA-MB-231 cells) were characterized. Transwell assay, wound healing and CCK-8 assay were employed to explore the effect of exosomal MMP-1 on the metastatic capability of TNBC cells in vitro. Human breast cancer lung metastasis model in nude mice was established to observe the effect of exosomal MMP-1 in vivo. Tissue microarray and blood samples of TNBC patients were applied to analyze the relevance between MMP-1 with metastasis. Results MDA-MB-231-HM cells secrete exosomes enriched MMP-1, which can be taken up and enhance invasion and migration activities of TNBC cells. After ingesting exosomes enriched with MMP-1, cells secrete more MMP-1, which may interact with membrane G protein receptor protease activated receptor 1 (PAR1), thereby initiating epithelial-mesenchymal transition (EMT) to enhance capability of migration and invasion. The expressions of MMP-1 and PAR1 in the metastases of the 231-HM-exo treated mice were both up-regulated. Clinically, the exosomal MMP-1 can be detected from serum of patients with metastasis at higher concentration than that in pre-operative patients. Moreover, in patients with multiple distant metastases, the level of exosomal MMP-1 is also higher than that in patients with single lesion. Conclusion MMP-1 from TNBC cells of high metastasis potential can promote the distant metastasis of transform those with low metastasis potential through PAR1-mediated EMT and is likely to be a potential molecular marker.

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