Autocrine TGF-β protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim

Hoshino, Yoichi; Katsuno, Yoko; Ehata, Shogo; Miyazono, Kohei

doi:10.1093/jb/mvq114

Cited by 51 publications

(47 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5B). Similar to previous reports (12,(20)(21)(22), TGF-β signaling was enhanced upon TGF-β2 treatment, indicating a functional TGF-β pathway in 4T1 cells. Conversely, inhibition of TGF-β signaling dramatically decreased phosphorylation of Akt and Twist1 (Fig.…”

supporting

confidence: 91%

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

et al. 2012

View full text Add to dashboard Cite

MARCH 2012 CANCER DISCOVERY | 249The BATTLE Trial: Personalizing Therapy for Lung Cancer RESEARCH ARTICLE efficiently induces EMT. In a clinically relevant orthotopic breast cancer mouse model, Twist1 expression is essential for the formation of lung metastasis (5). In hepatocelluar carcinomas, overexpression of Twist1 correlates with EMTassociated changes and metastasis (6). Twist1 expression can also negatively regulate programmed cell death (7) and overcome oncogene-induced senescence (4).These studies indicate that Twist1 plays multiple roles in the regulation of antiapoptosis and metastasis during tumor progression. Active Akt directly phosphorylates Twist1 on serine 42 (S42) and protects cells from apoptosis induced by DNA damage (8). Twist1 promotes crucial prometastatic roles in tumor development and is frequently associated with aberrant hyperactivation of phosphoinositide 3-kinase (PI3K)/Akt. This prompted us to explore whether phosphorylation of Twist1 by Akt is part of a molecular mechanism contributing to Twist1 activity in cancer and particularly in metastasis.We analyzed Twist1 phosphorylation in human cancer cell lines (with different genetic backgrounds) and invasive human breast tumors and addressed its functional importance in a mouse model of spontaneous breast tumor metastasis. We show that Twist1 is ubiquitously phosphorylated in invasive human breast tumors and is required for breast cancer lung metastasis in vivo. Twist1 phosphorylation supports metastasis by transcriptionally upregulating TGF-β2, leading to enhanced activation of TGF-βR/Smad2 signaling, and these effects could be significantly suppressed by the knockdown of TGF-β2 expression. These data suggest that Twist1 phosphorylation not only mediates a feedback loop allowing cross-talk with TGF-β to maintain hyperactivation of PI3K/Akt but can also potentiate cancer metastasis, at least in part, through enhanced TGF-β signaling in cancer cells. Collectively, our data uncover a novel mechanism Metastatic breast tumor cells display an epithelial-mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)-mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signalin...

show abstract

supporting

confidence: 91%

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Apart from its roles in EMT induction, TGFb has also been implicated in the ability of cancers to avoid conventional apoptotic pathways. In one such recent study, TGFb has been shown to protect breast cancer cells through a FOXC1-dependent mechanism through regulation of the pro-apoptotic protein bim (Hoshino et al, 2011). It is likely, therefore, that the contribution of FOXC1 to the aggressive phenotypes associated with BLBC may occur through several cooperating mechanisms.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

et al. 2011

View full text Add to dashboard Cite

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.

show abstract

“…Quantitative real-time RT-PCR (qRT-PCR) analysis and chromatin immunoprecipitation (ChIP)-qRT-PCR analysis were performed as previously described (7,8). Primer sequences are described in Supplementary Table S1.…”

Section: Quantitative Real-time Rt-pcr Analyses and Chromatin Immunopmentioning

confidence: 99%

“…Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed as previously described (7). Fluorescence was examined using a Leica DMI6000 B.…”

Section: Apoptosis Assaymentioning

confidence: 99%

Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

Autocrine TGF-β protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim

Cited by 51 publications

References 47 publications

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer

Contact Info

Product

Resources

About