scholarly journals Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yanying Huo ◽  
Pier Selenica ◽  
Amar H. Mahdi ◽  
Fresia Pareja ◽  
Kelly Kyker-Snowman ◽  
...  
Keyword(s):  
Mammary Tumor ◽  
Tumor Development ◽  
Tumor Formation ◽  
Conditional Knockout ◽  
Whole Exome ◽  
Cultured Human Cells ◽  
Brca1 Brca2 ◽  
Nulliparous Female ◽  
Inherited Mutations

AbstractInherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.

TMOD-26. MYC OVEREXPRESSION AND SMARCA4 LOSS IN GRANULE CELL PRECURSORS COOPERATE TO DRIVE MEDULLOBLASTOMA FORMATION IN MICE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi221-vi221
Author(s):  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Melanie Schoof ◽  
Catena Kresbach ◽  
Ulrich Schüller
Keyword(s):  
Granule Cell ◽  
Clinical Course ◽  
Tumor Development ◽  
Tumor Formation ◽  
Human Group ◽  
Group 4 ◽  
Small Cohort ◽  
Group 3 ◽  
Granule Cell Precursors

Abstract Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.

Estrogen Decreases Chemokine Levels in Murine Mammary Tissue: Implications for the Regulatory Role of MIP-1 Alpha and MCP-1/JE in Mammary Tumor Formation

Endocrine ◽  
2003 ◽  
Vol 22 (2) ◽  
pp. 161-168 ◽  
Author(s):  
Peter Fanti ◽  
Michael Nazareth ◽  
Robert Bucelli ◽  
Michael Mineo ◽  
Kathleen Gibbs ◽  
...  
Keyword(s):  
Mammary Tumor ◽  
Tumor Formation ◽  
Regulatory Role ◽  
Mammary Tissue

scholarly journals m6A Modification: A Double-Edged Sword in Tumor Development

2021 ◽  
Vol 11 ◽  
Author(s):  
Runnan Gao ◽  
Mujie Ye ◽  
Baihui Liu ◽  
Meng Wei ◽  
Duan Ma ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Tumor Development ◽  
Tumor Formation ◽  
Cancer Development ◽  
Research Progress ◽  
Biological Processes ◽  
Rna Methylation ◽  
Anti Cancer ◽  
Elevated Expression

Modification of m6A, as the most abundant mRNA modification, plays diverse roles in various biological processes in eukaryotes. Emerging evidence has revealed that m6A modification is closely associated with the activation and inhibition of tumor pathways, and it is significantly linked to the prognosis of cancer patients. Aberrant reduction or elevated expression of m6A regulators and of m6A itself have been identified in numerous tumors. In this review, we give a description of the dynamic properties of m6A modification regulators, such as methyltransferases, demethylases, and m6A binding proteins, and indicate the value of the balance between these proteins in regulating the expression of diverse genes and the underlying effects on cancer development. Furthermore, we summarize the “dual-edged weapon” role of RNA methylation in tumor progression and discuss that RNA methylation can not only result in tumorigenesis but also lead to suppression of tumor formation. In addition, we summarize the latest research progress on small-molecule targeting of m6A regulators to inhibit or activate m6A. These studies indicate that restoring the balance of m6A modification via targeting specific imbalanced regulators may be a novel anti-cancer strategy.

scholarly journals Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 341 ◽  
Author(s):  
Sonia Leon-Cabrera ◽  
Armando Vázquez-Sandoval ◽  
Emmanuel Molina-Guzman ◽  
Yael Delgado-Ramirez ◽  
Norma Delgado-Buenrostro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Activity Index ◽  
Tumor Development ◽  
Disease Activity Index ◽  
Tumor Stroma ◽  
Tumor Formation ◽  
Janus Kinase ◽  
Early Stages

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor–stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1−/− mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1−/− mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1−/− mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1−/− mice showed increased accumulation of Ly6G+Ly6C−CD11b+ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.

scholarly journals Beyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 346 ◽  
Author(s):  
Francisco Triana-Martínez ◽  
María Isabel Loza ◽  
Eduardo Domínguez
Keyword(s):  
Cell Fate ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Tumor Development ◽  
Tumor Formation ◽  
Cell Fates ◽  
Synthetic Lethal ◽  
Cell Phenotypes ◽  
The Impact

Here, we provide an overview of the importance of cellular fate in cancer as a group of diseases of abnormal cell growth. Tumor development and progression is a highly dynamic process, with several phases of evolution. The existing evidence about the origin and consequences of cancer cell fate specification (e.g., proliferation, senescence, stemness, dormancy, quiescence, and cell cycle re-entry) in the context of tumor formation and metastasis is discussed. The interplay between these dynamic tumor cell phenotypes, the microenvironment, and the immune system is also reviewed in relation to cancer. We focus on the role of senescence during cancer progression, with a special emphasis on its relationship with stemness and dormancy. Selective interventions on senescence and dormancy cell fates, including the specific targeting of cancer cell populations to prevent detrimental effects in aging and disease, are also reviewed. A new conceptual framework about the impact of synthetic lethal strategies by using senogenics and then senolytics is given, with the promise of future directions on innovative anticancer therapies.

scholarly journals Important roles of C5a and C5aR in tumor development and cancer treatment

2019 ◽  
Vol 136 ◽  
pp. 06012
Author(s):  
Wang Yuxuan
Keyword(s):  
Complement System ◽  
Tumor Therapy ◽  
Tumor Development ◽  
Tumor Formation ◽  
Complement Component ◽  
Innate Defense ◽  
And Migration ◽  
And Control ◽  
The Complement System

The complement system is part of the body's innate defense immune system, which can identify and eliminate invasive pathogenic microorganisms to maintain normal life activities. Complement Component 5a (C5a) is an active anaphylatoxin produced after complement system activation, closely related to tumor formation. C5a is highly expressed in a variety of tumors, and combines with its Complement Component 5a Receptor (C5aR) to increase the proliferation and migration of tumor cells. This review will comprehensively elaborate the important role of C5a/C5aR in the process of tumor genesis and development from the three aspects of signal transduction pathways related to tumor, C5a/C5aR and tumor formation, and C5a/C5aR inhibitors and tumor therapy. Finally, the principle of complement inhibition is used to inhibit tumor metastasis, reduce the rate of tumor diffusion, and control the trend of tumor deterioration.

scholarly journals Conditional Mutagenesis of Gata6 in SF1-Positive Cells Causes Gonadal-Like Differentiation in the Adrenal Cortex of Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1754-1767 ◽  
Author(s):  
Marjut Pihlajoki ◽  
Elisabeth Gretzinger ◽  
Rebecca Cochran ◽  
Antti Kyrönlahti ◽  
Anja Schrade ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adrenal Cortex ◽  
Adrenal Glands ◽  
Conditional Knockout ◽  
Hormonal Changes ◽  
Corticosterone Secretion ◽  
Steroidogenic Cell ◽  
Nulliparous Female ◽  
And Function

Abstract Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.

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