ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells

Langer, Ellen M.; Kendsersky, Nicholas D.; Daniel, Colin J.; Kuziel, Genevra; Pelz, Carl; Murphy, Kenneth M.; Capecchi, Mario R.; Sears, Rosalie C.

doi:10.1038/onc.2017.356

Cited by 50 publications

(36 citation statements)

References 63 publications

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“…also reported that ZEB1 is expressed in both tumor and stromal cells of the breast (40). ZEB1 directly increases the expression of proinflammatory cytokines such as IL6 and IL8, and it promotes vascular mimicry of breast cancer cells by remodeling extracellular matrix (33,41). We had previously demonstrated that cytokines such as TNF induce the expression of ZEB1 (42).…”

Section: Discussionmentioning

confidence: 93%

Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast

Nakshatri

Kumar

Burney

et al. 2019

Clinical Cancer Research

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Purpose: Genetic ancestry influences evolutionary pathways of cancers. However, whether ancestry influences cancer-induced field defects is unknown. The goal of this study was to utilize ancestry-mapped true normal breast tissues as controls to identify cancer-induced field defects in normal tissue adjacent to breast tumors (NATs) in women of African American (AA) and European (EA) ancestry.Experimental Design: A tissue microarray comprising breast tissues of ancestry-mapped 100 age-matched healthy women from the Komen Tissue Bank (KTB) at Indiana University (Indianapolis, IN) and tumor-NAT pairs from 100 women (300 samples total) was analyzed for the levels of ZEB1, an oncogenic transcription factor that is central to cell fate, mature luminal cell-enriched estrogen receptor alpha (ERa), GATA3, FOXA1, and for immune cell composition.Results: ZEB1 þ cells, which were localized surrounding the ductal structures of the normal breast, were enriched in the KTB-normal of AA compared with KTB-normal of EA women. In contrast, in EA women, both NATs and tumors compared with KTB-normal contained higher levels of ZEB1 þ cells. FOXA1 levels were lower in NATs compared with KTB-normal in AA but not in EA women. We also noted variations in the levels of GATA3, CD8 þ T cells, PD1 þ immune cells, and PDL1 þ cell but not CD68 þ macrophages in NATs of AA and EA women. ERa levels did not change in any of our analyses, pointing to the specificity of ancestrydependent variations.Conclusions: Genetic ancestry-mapped tissues from healthy individuals are required for proper assessment and development of cancer-induced field defects as early cancer detection markers. This finding is significant in light of recent discoveries of influence of genetic ancestry on both normal biology and tumor evolution. Conception and design: H. Nakshatri, C. D'Souza-Schorey Development of methodology: H. Nakshatri, M.L. Cox, G.E. Sandusky Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): H. Nakshatri, M.L. Cox, M. Jacobsen, A.M.V. Storniolo Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussionmentioning

confidence: 93%

Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast

Nakshatri

Kumar

Burney

et al. 2019

Clinical Cancer Research

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“…During this process, the secreted proteins fibronectin 1 (FN1) and serine protease inhibitor family E member 2 (SERPINE2) are essential for vascular mimicry (VM) in this system. These secreted factors were upregulated in mesenchymal cells by ZEB1-repressed miRNA clusters, promoting autocrine signaling, which was followed by increased VM in breast cancer cells [80]. In clinical studies, ZEB1 was found to be significantly associated with the depth of invasion, lymph node metastasis and TNM stage in digestive cancer patients, as well as in patients with breast cancer [81].…”

Section: Tumor Growth Metastasis and Emtmentioning

confidence: 99%

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer

Zhong

et al. 2020

J Transl Med

105

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Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc fingerhomeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-β, β-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

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“…Low-density lipoprotein receptor-related protein 1 (LRP1) and ITGB1 are receptors for these secreted proteins. Evidence shows that miR-183 regulates those autocrine signal and VM formation [51]. In addition, hypoxia-induced transcription factors (HIFs) are upregulated before angiogenesis due to hypoxia.…”

Section: Roles Of Mir-183 In Microangiogenesismentioning

confidence: 99%

MicroRNA-183 in Cancer Progression

Cao¹,

Di²,

Liang³

et al. 2020

J. Cancer

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MicroRNA -183(miR-183) is abnormally expressed in many kinds of tumors. It participates in the initiation and development of tumors. There are many pathways regulate the expression of miR-183. The action mechanism of miR-183 in cancer is very extensive, and contradictory conclusions are often drawn. It was upregulated in 18 kinds of cancer, downregulated in 6 kinds of cancer. In addition, there are seven types of cancer, both upregulated and downregulated reports can be found. Evidence showed that miR-183 can not only directly play the role of oncogene or antioncogene, but also regulate the expression of other oncogene or antioncogene in different cancer types. In this review, we discuss the regulator of miR-183 and summarized the expression of miR-183 in different cancers. We also counted the target genes of miR-183 and the functional roles they play. Furthermore, we focused on the roles of miR-183 in cell migration, cell invasion, epithelial-mesenchymal transition (EMT) and microangiogenesis, which play the most important roles in cancer processes. It sheds light on the likely reasons why miR-183 plays different roles in various cancers. In addition, miR-183 and its downstream effectors have the potential to be promising prognostic markers and therapeutic targets in cancer.

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ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells

Cited by 50 publications

References 63 publications

Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast

Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer

MicroRNA-183 in Cancer Progression

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