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 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 Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

2016 ◽  
Vol 113 (48) ◽  
pp. E7749-E7758 ◽  
Author(s):  
Roberto Rangel ◽  
Song-Choon Lee ◽  
Kenneth Hon-Kim Ban ◽  
Liliana Guzman-Rojas ◽  
Michael B. Mann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancer Subtype ◽  
Clinical Importance ◽  
Transposon Mutagenesis ◽  
Phosphatase And Tensin Homolog ◽  
Mesenchymal Transition ◽  
Tensin Homolog ◽  
Cancer Subtype

Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressorTRPS1. Down-regulation ofTRPS1in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression ofSERPINE1andSERPINB2and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

scholarly journals Two Faces of TGF-Beta1 in Breast Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Joanna Magdalena Zarzynska
Keyword(s):  
Breast Cancer ◽  
Cell Cycle Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Clinical Investigation ◽  
Mesenchymal Transition ◽  
Early Stages ◽  
New Therapeutic Approaches ◽  
Genes Encoding ◽  
Life Threatening

Breast cancer (BC) is potentially life-threatening malignancy that still causes high mortality among women. Scientific research in this field is focused on deeper understanding of pathogenesis and progressing of BC, in order to develop relevant diagnosis and improve therapeutic treatment. Multifunctional cytokine TGF-β1 is one of many factors that have a direct influence on BC pathophysiology. Expression of TGF-β1, induction of canonical and noncanonical signaling pathways, and mutations in genes encoding TGF-β1 and its receptors are correlated with oncogenic activity of this cytokine. In early stages of BC this cytokine inhibits epithelial cell cycle progression and promotes apoptosis, showing tumor suppressive effects. However, in late stages, TGF-β1 is linked with increased tumor progression, higher cell motility, cancer invasiveness, and metastasis. It is also involved in cancer microenvironment modification and promotion of epithelial to mesenchymal transition (EMT). This review summarizes the current knowledge on the phenomenon called “TGF-β1 paradox”, showing that better understanding of TGF-β1 functions can be a step towards development of new therapeutic approaches. According to current knowledge several drugs against TGF-β1 have been developed and are either in nonclinical or in early stages of clinical investigation.

scholarly journals Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

2019 ◽  
Author(s):  
Prahlad V. Raninga ◽  
Andy Lee ◽  
Debottam Sinha ◽  
Lan-feng Dong ◽  
Keshava K. Datta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Brain Metastases ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Proteasome Inhibition ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

AbstractLacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.One Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.

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 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 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.

Prolonged atrazine exposure beginning in utero and adult uterine morphology in mice

2021 ◽  
pp. 1-10
Author(s):  
Meaghan J. Griffiths ◽  
Amy L. Winship ◽  
Jessica M. Stringer ◽  
Elyse O. Swindells ◽  
Alesia P. Harper ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oestrogen Receptor ◽  
Endometrial Hyperplasia ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Metabolism ◽  
In Utero ◽  
Receptor Expression ◽  
Mesenchymal Transition ◽  
Pregnant Mice ◽  
Emt Markers

Abstract Through drinking water, humans are commonly exposed to atrazine, a herbicide that acts as an endocrine and metabolic disruptor. It interferes with steroidogenesis, including promoting oestrogen production and altering cell metabolism. However, its precise impact on uterine development remains unknown. This study aimed to determine the effect of prolonged atrazine exposure on the uterus. Pregnant mice (n = 5/group) received 5 mg/kg body weight/day atrazine or DMSO in drinking water from gestational day 9.5 until weaning. Offspring continued to be exposed until 3 or 6 months of age (n = 5–9/group), when uteri were collected for morphological and molecular analyses and steroid quantification. Endometrial hyperplasia and leiomyoma were evident in the uteri of atrazine-exposed mice. Uterine oestrogen concentration, oestrogen receptor expression, and localisation were similar between groups, at both ages (P > 0.1). The expression and localisation of key epithelial-to-mesenchymal transition (EMT) genes and proteins, critical for tumourigenesis, remained unchanged between treatments, at both ages (P > 0.1). Hence, oestrogen-mediated changes to established EMT markers do not appear to underlie abnormal uterine morphology evident in atrazine exposure mice. This is the first report of abnormal uterine morphology following prolonged atrazine exposure starting in utero, it is likely that the abnormalities identified would negatively affect female fertility, although mechanisms remain unknown and require further study.

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 Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 259
Author(s):  
Monish Ram Makena ◽  
Myungjun Ko ◽  
Donna Kimberly Dang ◽  
Rajini Rao
Keyword(s):  
Breast Cancer ◽  
Secretory Pathway ◽  
Histone Deacetylase Inhibitors ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Subtype ◽  
Survival Prognosis ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Canonical Wnt

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

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