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24 April 2020
Cellular Plasticity in Breast Cancer Progression and Therapy
Deguang Kong
1 more and 
Heide L. Ford

With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.

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Pleiotropic roles of ZEB1 in the cell plasticity, EMT, and therapy resistance. The ZEB1 represents a core transcriptional factor and central determinant of cell fate which controls fundamental intracellular processes including cell plasticity, EMT, or therapy resistance. Downstream signaling pathways triggered by ZEB1, regulate the activity of the proteins and miRNAs involved in cell differentiation, proliferation, or motility. ZEB1 overexpression is accompanied by overall changeover of the cell phenotype, higher tumorigenic potential, and increased migratory character. ZEB1 also promotes immune escape as well as contributes to the formation of a pre-metastatic niche. Given the tumor heterogeneity, ZEB1 plays an important role in the stemness of cancer cells and increased radio- and chemoresistance. Green and red arrows illustrate major activating or inhibitory effects of ZEB1, respectively. CSCs, cancer stem cells; EMT, epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition; DDR, DNA damage response; HR, homologous recombination. Created with Biorender.com.
Mini Review
19 March 2020

The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.

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142 citations
Review
20 December 2019
Mitochondrial Involvement in Migration, Invasion and Metastasis
Tatiana V. Denisenko
1 more and 
Boris Zhivotovsky
Schematic representation of mitochondrial involvement in metastasis. Arrows or blunt ends indicate activation or inhibition, respectively. Red arrow indicates increased level. ∗ - function depends on the tumor type. OXPHOS, oxidative phosphorylation; ER, endoplasmic reticulum; ROS, reactive oxygen species. For details, see text. Figure is created using BioRender.

Mitochondria in addition to be a main cellular power station, are involved in the regulation of many physiological processes, such as generation of reactive oxygen species, metabolite production and the maintenance of the intracellular Ca2+ homeostasis. Almost 100 years ago Otto Warburg presented evidence for the role of mitochondria in the development of cancer. During the past 20 years mitochondrial involvement in programmed cell death regulation has been clarified. Moreover, it has been shown that mitochondria may act as a switchboard between various cell death modalities. Recently, accumulated data have pointed to the role of mitochondria in the metastatic dissemination of cancer cells. Here we summarize the modern knowledge concerning the contribution of mitochondria to the invasion and dissemination of tumor cells and the possible mechanisms behind that and attempts to target metastatic cancers involving mitochondria.

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106 citations
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