Bidirectional regulatory crosstalk between cell context and genomic aberrations shapes breast tumorigenesis

: Breast cancer has a multifactorial etiology and, among the main causal factors, the dietary profile stands out, mainly the components of the pro-inflammatory diet and the interaction with genetic characteristics. In this sense, deciphering the molecular networks involved in the proliferation of cancer cells in breast tissue can determine ways of action of organic compounds that contain the pathogenesis of cancer, such as vitamin A and analogues, as well as their possible mechanisms of modulation of breast tumorigenesis. This is a review study conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and by consulting the PubMed and Web of Science databases and including articles from the last five years, published in Portuguese, English and Spanish. 126 articles were obtained, of which 13 were selected for full reading and 6 were included in the study for meeting the eligibility criteria. The results of the compiled studies demonstrate the role that some retinol-binding proteins play in their metabolism, as well as in differentiation, cell proliferation and inflammation. Although controversial, the results point to the use of these structures as possible prognostic markers. The need for further studies in humans is also emphasized in order to assess the main effects of vitamin isoforms on tumor activity.

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MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis

Scientific Reports ◽

10.1038/s41598-021-85056-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Diala Kantar ◽

Emilie Bousquet Mur ◽

Maicol Mancini ◽

Vera Slaninova ◽

Yezza Ben Salah ◽

...

Keyword(s):

Protein Kinase ◽

Cancer Progression ◽

Hippo Pathway ◽

Intercellular Junctions ◽

Cell Polarization ◽

Actin Binding ◽

Breast Cancers ◽

Epithelial Cancer ◽

Breast Tumorigenesis ◽

Stress Pathway

AbstractAlterations to cell polarization or to intercellular junctions are often associated with epithelial cancer progression, including breast cancers (BCa). We show here that the loss of the junctional scaffold protein MAGI1 is associated with bad prognosis in luminal BCa, and promotes tumorigenesis. E-cadherin and the actin binding scaffold AMOTL2 accumulate in MAGI1 deficient cells which are subjected to increased stiffness. These alterations are associated with low YAP activity, the terminal Hippo-pathway effector, but with an elevated ROCK and p38 Stress Activated Protein Kinase activities. Blocking ROCK prevented p38 activation, suggesting that MAGI1 limits p38 activity in part through releasing actin strength. Importantly, the increased tumorigenicity of MAGI1 deficient cells is rescued in the absence of AMOTL2 or after inhibition of p38, demonstrating that MAGI1 acts as a tumor-suppressor in luminal BCa by inhibiting an AMOTL2/p38 stress pathway.

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Arginine Methyltransferase PRMT1 Regulates p53 Activity in Breast Cancer

Life ◽

10.3390/life11080789 ◽

2021 ◽

Vol 11 (8) ◽

pp. 789

Author(s):

Li-Ming Liu ◽

Qiang Tang ◽

Xin Hu ◽

Jing-Jing Zhao ◽

Yuan Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Asymmetric Dimethylarginine ◽

Human Cancer ◽

Specific Inhibitor ◽

Dependent Manner ◽

Breast Tumorigenesis ◽

Stress Signals

The protein p53 is one of the most important tumor suppressors, responding to a variety of stress signals. Mutations in p53 occur in about half of human cancer cases, and dysregulation of the p53 function by epigenetic modifiers and modifications is prevalent in a large proportion of the remainder. PRMT1 is the main enzyme responsible for the generation of asymmetric-dimethylarginine, whose upregulation or aberrant splicing has been observed in many types of malignancies. Here, we demonstrate that p53 function is regulated by PRMT1 in breast cancer cells. PRMT1 knockdown activated the p53 signal pathway and induced cell growth-arrest and senescence. PRMT1 could directly bind to p53 and inhibit the transcriptional activity of p53 in an enzymatically dependent manner, resulting in a decrease in the expression levels of several key downstream targets of the p53 pathway. We were able to detect p53 asymmetric-dimethylarginine signals in breast cancer cells and breast cancer tissues from patients, and the signals could be significantly weakened by silencing of PRMT1 with shRNA, or inhibiting PRMT1 activity with a specific inhibitor. Furthermore, PRMT1 inhibitors significantly impeded cell growth and promoted cellular senescence in breast cancer cells and primary tumor cells. These results indicate an important role of PRMT1 in the regulation of p53 function in breast tumorigenesis.

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Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology

npj Precision Oncology ◽

10.1038/s41698-021-00155-6 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Ianthe A. E. M. van Belzen ◽

Alexander Schönhuth ◽

Patrick Kemmeren ◽

Jayne Y. Hehir-Kwa

Keyword(s):

Intratumor Heterogeneity ◽

Precision Oncology ◽

Single Nucleotide Variants ◽

Full Spectrum ◽

Single Nucleotide ◽

Sequencing Technologies ◽

Cancer Genomes ◽

Genomic Aberrations

AbstractCancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection. Biological and computational challenges confound SV detection in cancer samples, including intratumor heterogeneity, polyploidy, and distinguishing tumor-specific SVs from germline and somatic variants present in healthy cells. Classification of tumor-specific SVs is challenging due to inconsistencies in detected breakpoints, derived variant types and biological complexity of some rearrangements. Full-spectrum SV detection with high recall and precision requires integration of multiple algorithms and sequencing technologies to rescue variants that are difficult to resolve through individual methods. Here, we explore current strategies for integrating SV callsets and to enable the use of tumor-specific SVs in precision oncology.

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