A Novel SASH1-IQGAP1-E-Cadherin Signal Cascade Mediates Breast Cancer Metastasis

HER2 (human epidermal growth factor receptor 2) activation is critical in breast cancer development. HER2 promotes cell proliferation, angiogenesis, survival, and metastasis by activation of PI3K/Akt, Ras/MEK/ERK, and JAK/STAT pathways. However, beyond these signaling molecules, the key proteins underlining HER2-mediated metastasis remain elusive. ATF4 (Activating transcription factor 4), a critical regulator in unfolded protein response (UPR), is implicated in cell migration and tumor metastasis. In this study, we demonstrate that HER2 upregulated ATF4 expression at both mRNA and protein levels, resulting in cell migration increased. In addition, ATF4 upregulated ZEB1 (Zinc finger E-box-binding homeobox 1) and suppressed E-cadherin expression resulting in promoting cell migration. Restoration of E-cadherin expression effectively inhibited HER2- or ATF4-mediated cell migration. In addition, upregulated expression of ATF4 was found in HER2-positive breast cancer specimens. Together, this study demonstrates that ATF4-ZEB1 is important for HER2-mediated cell migration and suggests that ATF4-ZEB1 may be potential therapeutic targets for breast cancer metastasis.

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Peran Matriks Metalloproteinase 8 Pada Metastasis Sel Kanker Payudara

Indonesian Journal of Health Science ◽

10.54957/ijhs.v1i2.52 ◽

2021 ◽

Vol 1 (2) ◽

pp. 31-35

Author(s):

Mike Permata Sari

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Normal Breast ◽

Breast Cancer Patients ◽

Direct Role ◽

Stat3 Signaling Pathway ◽

Extracellular Proteinases ◽

Breast Cells ◽

E Cadherin

MMP-8 merupakan protease yang diproduksi oleh neutrofil dan berperan dalam degradasi kolagen yang terdapat pada jaringan ikat pada mamalia. Pada manusia, protein MMP-8 disandi oleh gen MMP-8. Pada umumnya, MMP disekresi dalam bentuk proprotein yang diaktifkan ketika dipecah oleh proteinase ekstraseluler. Peningkatan Ekspresi MMP-8 berlebih pada penderita kanker payudara di fase yang berbeda, peningkatan ekspresi MMP-8 tidak ditemukan pada sel payudara normal. MMP-8 memiliki substrat yang berbeda dengan MMP-2 dan MMP-9 yang berperan langsung dalam penyebab metastasis sel kanker payudara ke organ lain. Peran MMP-8 terhadap kanker payudara telah dilaporkan oleh penelitian sebelumnya bahwa MMP-8 mampu memicu metastasis kanker payudara melalui peningkatan sitokin proinflamasi yaitu IL-6 dan IL-8. IL-6 dan IL-8 menginduksi metastasis melalui jalur persinyalan JAK/STAT3 yang akan mengaktifkan snail/slug/twist yang akan menekan ekspresi E-cadherin, selain itu IL-6 dan IL-8 memicu sintesis VEGF sehingga mengakibatkan pembentukan pembuluh darah baru. MMP-8 is a protease produced by neutrophils and plays a role in the degradation of collagen found in connective tissue in mammals. In humans, the MMP-8 protein is encoded by the MMP-8 gene. In general, MMPs are secreted in the form of proproteins that are activated when cleaved by extracellular proteinases. MMP-8 Ekspression increased in breast cancer patients at different stages, but it is not happenin normal breast cells. MMP-8 has a different substrate with MMP-2 and MMP-9 which play a direct role in causing breast cancer cell metastasis to other organs. The role of MMP-8 in breast cancer has been reported by previous studies that MMP-8 is able to trigger breast cancer metastasis through an increase in proinflammatory cytokines,such as IL-6 and IL-8. IL-6 and IL-8 induce metastasis through the JAK/STAT3 signaling pathway which will activate snail/slug/twist which will suppress E-cadherin expression, in addition IL-6 and IL-8 trigger VEGF synthesis, resulting in the formation of new blood vessels.

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MicroRNA-10b targets E-cadherin and modulates breast cancer metastasis

Medical Science Monitor ◽

10.12659/msm.883262 ◽

2012 ◽

Vol 18 (8) ◽

pp. BR299-BR308 ◽

Cited By ~ 43

Author(s):

Yong Liu ◽

Jing Zhao ◽

Pei-Ying Zhang ◽

Yu Zhang ◽

San-Yuan Sun ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

E Cadherin

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Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial-mesenchymal transition

10.1101/443663 ◽

2018 ◽

Author(s):

Sabrina Tripolt ◽

Vanessa M. Knab ◽

Heidi A. Neubauer ◽

Dominik P. Elmer ◽

Fritz Aberger ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Cancer Metastasis ◽

Kinase Inhibitor ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Stat3 Signaling ◽

E Cadherin

AbstractThe opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of δ-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

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