Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Takahashi, Fumiyuki; Chiba, Naokazu; Tajima, Ken; Hayashida, Tetsu; Shimada, Takashi; Takahashi, Mirei; Moriyama, Hitomi; Brachtel, Elena F.; Edelman, Elena J.; Ramaswamy, Shivapriya; Maheswaran, Shyamala

doi:10.1038/onc.2011.24

Cited by 55 publications

(60 citation statements)

References 65 publications

(124 reference statements)

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“…It was noted that tumors with nodepositive exhibited significantly lower TIS21 /BTG2/Pc3 expression than normal tissues, but not in node-negative tumors (P = 0.003 and P = 0.242, respectively, Supplementary Figure S10b). The data are well accordant with the reports on invasion via blood and lymphatics, 59,60 suggesting that TIS21 /BTG2/Pc3 has an important role in cancer progression of invasive-metastatic phenotypes in breast cancers. Noticeably, targeting TIS21 /BTG2/Pc3 expression by miR-21 61 shifts prostate basal cells toward luminal type and inducing epithelial-to-mesenchymal transition features, indicating the promotion of cancer migration/invasion through downregulation of TIS21 /BTG2/Pc3 expression by microRNAs.…”

Section: Discussionsupporting

confidence: 90%

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

Jung

et al. 2015

Oncogene

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The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of actin-related biological processes. We have previously reported that tumor suppressor TIS21(/BTG2/Pc3) (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21(/BTG2/Pc3) downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21(/BTG2/Pc3)-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21(/BTG2/Pc3)-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21(/BTG2/Pc3)-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes.

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Section: Discussionsupporting

confidence: 90%

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

Jung

et al. 2015

Oncogene

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“…The Cnot2 module also contained at least four previously identified regulators of tumor progression: the metastasis susceptibility gene, Arid4b, its protein interaction partner, Sin3a, Luc7l, and the antiproliferative cell cycle component Btg2 (Crawford et al 2008b;Takahashi et al 2011;Winter et al 2012;Das et al 2013). Our laboratory validated the direct role of both Arid4b and Luc7l using genetic and in vivo modeling of metastasis (Crawford et al 2008b;Winter et al 2012).…”

Section: Discussionmentioning

confidence: 65%

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Faraji

et al. 2013

Genome Res.

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Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. Small RNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis.[Supplemental material is available for this article.]Metastasis is a systemic disease responsible for the majority of cancer-related mortality and is influenced by both tumor cell-autonomous and host-derived factors. Its complexity is deepened by involvement of not only stochastic genomic and epigenetic events but also by inherited predisposition (Lifsted et al. 1998;Crawford et al. 2006). As a result, despite identification and characterization of individual genes, cellular and developmental processes associated with metastasis, understanding of the metastatic cascade and the interconnectivity of individual factors remains limited. The elucidation of higher-order networks underlying metastasis will therefore likely improve prognostication and intervention strategies by identifying molecular nodes central to tumor cell dissemination and colonization.Recent advances in global gene expression profiling and computational science have provided the basis for understanding cancer biology at a systems level (Quigley et al. 2009). Knowledge of both tumor subtypes (Perou et al. 2000) and patient prognosis has been enhanced by systems-based approaches. This knowledge may significantly change clinical practice by enabling the development of precision treatments based on mol...

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“…It has previously been found to be down-regulated by ER and to inhibit breast cancer cell growth (37). Loss of expression of this gene is correlated with a poor prognosis in patients with breast cancer and was predictive of tumor grade and size, invasion, recurrence, and overall survival (38). These findings suggest that BTG2 might be a useful pharmacodynamic biomarker for the action of ER antagonists such as fulvestrant that potentiate p53-dependent cell death.…”

Section: Discussionmentioning

confidence: 88%

Estrogen receptor prevents p53-dependent apoptosis in breast cancer

Bailey

Shin

Westerling

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

131

129

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More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER− breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild-type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genomewide approaches, we have addressed the mechanism by which ER antagonizes the proapoptotic function of p53. Interestingly, both ER agonists such as estradiol and the selective ER modulator (SERM) tamoxifen promote p53 antagonism. In contrast, the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This inhibition works through a mechanism involving the modulation of a subset of p53 and ER target genes that can predict the relapse-free survival of patients with ER+ breast cancer. These findings suggest an improved strategy for the treatment of ER+ breast cancer using antagonists that completely block ER action together with drugs that activate p53-mediated cell death.cistrome | DNA damage | nuclear receptor | nutlin | doxorubicin

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Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Cited by 55 publications

References 65 publications

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Estrogen receptor prevents p53-dependent apoptosis in breast cancer

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