scholarly journals Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

Oncogene ◽  
2021 ◽  
Author(s):  
M. Guy Roukens ◽  
Cynthia L. Frederiks ◽  
Danielle Seinstra ◽  
Luca Braccioli ◽  
Antoine A. Khalil ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Tumor ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Patterns ◽  
Tumor Development ◽  
Cell Types ◽  
Dependent Manner ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Genetic Mouse Model

AbstractIn breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells.

scholarly journals Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1058 ◽  
Author(s):  
Gener ◽  
Rafael ◽  
Seras-Franzoso ◽  
Perez ◽  
Pindado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Phenotypic Change ◽  
Primary Tumors ◽  
Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

scholarly journals Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways

2021 ◽  
Vol 14 (11) ◽  
pp. 1122
Author(s):  
Michelle M. Williams ◽  
Sabrina A. Hafeez ◽  
Jessica L. Christenson ◽  
Kathleen I. O’Neill ◽  
Nia G. Hammond ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Clinical Investigation ◽  
Cell Metabolism ◽  
Breast Cancer Subtype ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Response To Chemotherapy ◽  
Metastatic Sites

Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.

scholarly journals IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

2012 ◽  
Vol 20 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Nikki A Ford ◽  
Nomeli P Nunez ◽  
Valerie B Holcomb ◽  
Stephen D Hursting
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Mammary Tumor ◽  
Murine Model ◽  
Epithelial To Mesenchymal Transition ◽  
Luminal Breast Cancer ◽  
Growth Factor Signaling ◽  
Mesenchymal Transition ◽  
Chemokine Expression ◽  
Mammary Tumor Growth

Luminal breast tumors with little or no estrogen receptor α expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.

scholarly journals Senescent Breast Luminal Cells Promote Carcinogenesis through Interleukin-8-Dependent Activation of Stromal Fibroblasts

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Huda H. Al-Khalaf ◽  
Hazem Ghebeh ◽  
Rabia Inass ◽  
Abdelilah Aboussekhra
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Normal Breast ◽  
Dependent Manner ◽  
Stromal Fibroblasts ◽  
Mesenchymal Transition ◽  
Lamin B1 ◽  
Luminal Cells

ABSTRACT Aging and stress promote senescence, which has intrinsic tumor suppressor functions and extrinsic tumor promoting properties. Therefore, it is of utmost importance to delineate the effects of senescence inducers on the various types of cells that compose the different organs. We show here that primary normal breast luminal (NBL) cells are more sensitive than their corresponding stromal fibroblasts to proliferative as well as oxidative damage-induced senescence. Like fibroblasts, senescent NBL cells secreted elevated amounts of various cytokines, including interleukin-6 (IL-6) and IL-8, and expressed high levels of p16, p21, and p53, while lamin B1 was downregulated. When senescent, luminal cells activated stromal fibroblasts in an IL-8-dependent manner, through the activation of the STAT3 pathway. These myofibroblasts promoted the epithelial-to-mesenchymal transition and the stemness processes in breast cancer cells in a paracrine manner both in vitro and in a breast cancer animal model. These results show the role of senescent breast luminal cells in promoting the inflammatory/carcinogenic microenvironment through the activation of fibroblasts in an IL-8-dependent manner.

scholarly journals The zinc finger E-box binding homeobox transcriptional repressor ZEB1 is differentially expressed in the metastases of patients with breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Tumors ◽  
Differentially Expressed ◽  
Tissue Type ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Mrna Quantification ◽  
E Box ◽  
Zeb1 Expression

Metastasis is a major problem in patients with breast cancer (1). We analyzed published microarray (2) and multiplexed mRNA quantification (3) datasets to identify transcription factors whose expression changed most significantly between primary tumors in patients with breast cancer and metastatic tissues. We identified ZEB1 as differentially expressed when comparing the transcriptomes of primary tumors of the breast to the metastases they generate (2). Analysis of a separate multiplexed mRNA quantification dataset uncovered similar differential expression of ZEB1 in metastases compared to primary breast tumors (3). ZEB1 expression has been reported as important for metastases and for the epithelial to mesenchymal transition in cancer (4-9); we found in this study, however, that ZEB1 was expressed at significantly lower levels in metastases across tissue type when compared to primary breast tumors.

scholarly journals miR-34a and miR-200c Have an Additive Tumor-Suppressive Effect on Breast Cancer Cells and Patient Prognosis

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 267
Author(s):  
Behzad Mansoori ◽  
Nicola Silvestris ◽  
Ali Mohammadi ◽  
Vahid Khaze ◽  
Elham Baghbani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Development ◽  
Suppressive Effect ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Cellular Effects ◽  
Normal Tissues ◽  
Therapeutic Tools

Breast cancer is the most common women’s malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles in regulating key cellular processes by suppressing gene expression. However, additive opportunities involving miRNAs have been underexplored. For example, both miR-34a and miR-200c individually suppress the development of different types of cancer, but the cellular effects of their combined actions remain unknown. Here, we show that miR-34a and miR-200c levels are reduced in breast tumors compared to adjacent normal tissues and that this additively predicts poor patient survival. In addition, in cell lines, miR-34a and miR-200c additively induce apoptosis and cell cycle arrest, while also inhibiting proliferation, invasion, migration, stemness and epithelial-to-mesenchymal transition (EMT). Mechanistically, both miRNA-34a and miR-200c directly target HIF1-α and subsequently downregulate VEGFR, MMP9 and CXCR4, although combined miRNA-34a and miR-200c delivery suppresses mouse xenograft tumor development as effectively as individual delivery. We establish a model, supported by in vitro and clinical data, which collectively suggest that the co-delivery of miR-34a and miR-200c represents a promising novel therapeutic strategy for breast cancer patients.

scholarly journals Dissection of major cancer gene variants in subsets of circulating tumor cells in advanced breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stella D’Oronzo ◽  
Domenica Lovero ◽  
Raffaele Palmirotta ◽  
Luigia Stefania Stucci ◽  
Marco Tucci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Stage Iv ◽  
Metastatic Potential ◽  
Gene Variants ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Genomic Markers

AbstractEnumeration of circulating tumor cells (CTCs) may reflect the metastatic potential of breast cancer (BC). By using the DEPArray, we investigated CTCs with respect to their epithelial-to-mesenchymal transition phenotype and compared their genomic heterogeneity with tissue biopsies. Seventeen stage IV BC patients were enrolled. Pre-enriched CTC suspensions were stained with fluorescent-labeled antibodies to epithelial (E) and mesenchymal (M) markers. CTC samples were processed by DEPArray system and clustered in relation to their markers. DNA from CTCs, as well as from primary tumor samples, was sequenced by next generation sequencing to assess the mutational state of 50 major cancer-related genes. We identified four different CTC subsets that harbored different gene variants. The most heterogenous CTC subsets included the M+/E− phenotype, which, however, expressed only 7 repeatedly mutated genes, while in the M−/E+ subset multiple mutations affected only 2 out of 50 genes. When matching all gene variants among CTC subsets, a small number of mutations was shared by only 4 genes, namely ATM, FGFR3, PIK3CA, and TP53 that, however, were absent in primary tumors. Our results postulate that the detected mutations in all CTC subsets may be considered as genomic markers of metastatic dissemination to be investigated during early stages of BC.

scholarly journals The Role of Tumor Microenvironment and Impact of Cancer Stem Cells on Breast Cancer Progression and Growth

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Nenad Markovic ◽  
Ana Lukovic ◽  
Nebojsa Arsenijevic ◽  
Srdjan Ninkovic ◽  
Biljana Ljujic
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Cytotoxic Agents ◽  
Molecular Characteristics ◽  
Mesenchymal Transition

Abstract Breast cancer is not only a mass of genetically abnormal tissue in the breast. This is a well-organized system of a complex heterogeneous tissue. Cancer cells produce regulatory signals that stimulate stromal cells to proliferate and migrate; then, stromal elements respond to these signals by releasing components necessary for tumor development that provide structural support, vasculature, and extracellular matrices. Developing tumors can mobilize a variety of cell types from both local and distant niches via secret chemical factors derived from cancer cells themselves or neighboring cells disrupted by growing neoplasm, such as fibroblasts, immune inflammatory cells, and endothelial cells. CSCs are a group of very few cells that are tumorigenic (able to form tumors) and are defined as those cells within a tumor that can self-renew and lead to tumorigenesis. BCSCs represent a small population of cells that have stem cell characteristics and are related to breast cancer. There are different theories about the origin of BCSCs. BCSCs are responsible for breast carcinoma metastasis. Usually, there is a metastatic spread to the bones, and rarely to the lungs and liver. A phenomenon that allows BCSCs to make the transition from epithelial to mesenchymal expression and thus avoid the effect of cytotoxic agents is the epithelial-mesenchymal transition (EMT). During this process, cells change their molecular characteristics in terms of loss of epithelial characteristics taking the mesenchymal phenotype. This process plays a key role in the progression, invasion, and metastasis of breast tumors.

scholarly journals Identification and Roles of miR-29b-1-3p and miR29a-3p-Regulated and Non-Regulated lncRNAs in Endocrine-Sensitive and Resistant Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3530
Author(s):  
Penn Muluhngwi ◽  
Carolyn M. Klinge
Keyword(s):  
Breast Cancer ◽  
Cancer Survival ◽  
Expression Patterns ◽  
Endocrine Resistance ◽  
Estrogen Receptor Α ◽  
Resistant Cell ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Non Coding Rnas ◽  
Mcf 7

Despite improvements in the treatment of endocrine-resistant metastatic disease using combination therapies in patients with estrogen receptor α (ERα) primary tumors, the mechanisms underlying endocrine resistance remain to be elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNA) and long non-coding RNAs (lncRNA), are targets and regulators of cell signaling pathways and their exosomal transport may contribute to metastasis. Previous studies have shown that a low expression of miR-29a-3p and miR-29b-3p is associated with lower overall breast cancer survival before 150 mos. Transient, modest overexpression of miR-29b1-3p or miR-29a-3p inhibited MCF-7 tamoxifen-sensitive and LCC9 tamoxifen-resistant cell proliferation. Here, we identify miR-29b-1/a-regulated and non-regulated differentially expressed lncRNAs in MCF-7 and LCC9 cells using next-generation RNA seq. More lncRNAs were miR-29b-1/a-regulated in LCC9 cells than in MCF-7 cells, including DANCR, GAS5, DSCAM-AS1, SNHG5, and CRND. We examined the roles of miR-29-regulated and differentially expressed lncRNAs in endocrine-resistant breast cancer, including putative and proven targets and expression patterns in survival analysis using the KM Plotter and TCGA databases. This study provides new insights into lncRNAs in endocrine-resistant breast cancer.

scholarly journals Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

2021 ◽  
Vol 38 (2) ◽  
Author(s):  
Wenqian Zheng ◽  
Jinhui Hu ◽  
Yiming Lv ◽  
Bingjun Bai ◽  
Lina Shan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Dependent Signaling Pathway ◽  
Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

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