scholarly journals Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression

2021 ◽  
Author(s):  
Fabiana Lüönd ◽  
Stefanie Tiede ◽  
Gerhard Christofori
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumour Cell ◽  
Current Knowledge ◽  
Tumour Progression ◽  
Malignant Tumour ◽  
Cell Plasticity ◽  
Tumour Heterogeneity ◽  
Extrinsic Factors ◽  
Mesenchymal Transition

AbstractHeterogeneity within a tumour increases its ability to adapt to constantly changing constraints, but adversely affects a patient’s prognosis, therapy response and clinical outcome. Intratumoural heterogeneity results from a combination of extrinsic factors from the tumour microenvironment and intrinsic parameters from the cancer cells themselves, including their genetic, epigenetic and transcriptomic traits, their ability to proliferate, migrate and invade, and their stemness and plasticity attributes. Cell plasticity constitutes the ability of cancer cells to rapidly reprogramme their gene expression repertoire, to change their behaviour and identities, and to adapt to microenvironmental cues. These features also directly contribute to tumour heterogeneity and are critical for malignant tumour progression. In this article, we use breast cancer as an example of the origins of tumour heterogeneity (in particular, the mutational spectrum and clonal evolution of progressing tumours) and of tumour cell plasticity (in particular, that shown by tumour cells undergoing epithelial-to-mesenchymal transition), as well as considering interclonal cooperativity and cell plasticity as sources of cancer cell heterogeneity. We review current knowledge on the functional contribution of cell plasticity and tumour heterogeneity to malignant tumour progression, metastasis formation and therapy resistance.

scholarly journals Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

2019 ◽  
Author(s):  
Fatima Valdes-Mora ◽  
Robert Salomon ◽  
Brian Gloss ◽  
Andrew MK. Law ◽  
Lesley Castillo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Cells ◽  
Tumour Progression ◽  
Breast Cancer Subtype ◽  
Luminal Breast Cancer ◽  
Luminal Progenitor ◽  
Mesenchymal Transition ◽  
Basal Breast Cancer ◽  
Cancer Subtype

AbstractBoth luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal–like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including epithelial-to-mesenchymal transition (EMT), hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our high-resolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires an aberrant post-lactation developmental program that involves both cancer cells and cells from the TME, to shift molecular subtype and promote tumour progression, with potential to explain the increased risk and poor prognosis of breast cancer associated to childbirth.

scholarly journals Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yawei Wang ◽  
Yingying Sun ◽  
Chao Shang ◽  
Lili Chen ◽  
Hongyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Mechanism ◽  
Regulation Mechanism ◽  
Rna Helicases ◽  
Mesenchymal Transition ◽  
Dead Box ◽  
E Cadherin

AbstractRing1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

scholarly journals Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3143
Author(s):  
Sergey E. Parfenyev ◽  
Sergey V. Shabelnikov ◽  
Danila Y. Pozdnyakov ◽  
Olga O. Gnedina ◽  
Leonid S. Adonin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Critical Role ◽  
Malignant Neoplasm ◽  
Malignant Neoplasms ◽  
Breast Cancer Patients ◽  
Survival Prognosis ◽  
Mesenchymal Transition ◽  
Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

scholarly journals Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 89
Author(s):  
Ha Thi Thu Do ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

scholarly journals A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiraporn Kantapan ◽  
Siwaphon Paksee ◽  
Aphidet Duangya ◽  
Padchanee Sangthong ◽  
Sittiruk Roytrakul ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Mammosphere Formation ◽  
Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

scholarly journals Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition

2011 ◽  
Vol 102 (6) ◽  
pp. 1151-1157 ◽  
Author(s):  
Xiaoyan Li ◽  
Xiaoli Kong ◽  
Qiang Huo ◽  
Haiyang Guo ◽  
Shi Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1079
Author(s):  
Manuela Zangrossi ◽  
Patrizia Romani ◽  
Probir Chakravarty ◽  
Colin D.H. Ratcliffe ◽  
Steven Hooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Lung Epithelial Cells ◽  
Late Relapse ◽  
Alveolar Type ◽  
Type I ◽  
Extrinsic Factors ◽  
Lung Epithelial

Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.

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