FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27

Zhao, Yifan; Zhao, Jingyu; Hong, Yu; Hu, Keshi; Shen, Hao; Guo, Zhenggang; Su, Xiaojun

doi:10.1016/j.bbrc.2014.11.064

Cited by 63 publications

(83 citation statements)

References 29 publications

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“…Knockdown of FOXD1 significantly inhibited proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo, and increased the apoptosis rates of NSCLC cells. The results were consistent with other studies, which showed significant growth inhibition in several cancer cell types [7,10,21]. In breast cancer, it was suggested that FOXD1 induces the G1/S transition and promotes the cell cycle progression by down-regulation of p27 expression [10].…”

Section: Discussionsupporting

confidence: 82%

“…The results were consistent with other studies, which showed significant growth inhibition in several cancer cell types [7,10,21]. In breast cancer, it was suggested that FOXD1 induces the G1/S transition and promotes the cell cycle progression by down-regulation of p27 expression [10]. In glioma, reduced expression of FOXD1 was associated with the inhibition of glioma cell proliferation, cell survival and migration, implying that FOXD1 is an oncogene in glioma [21].…”

Section: Discussionsupporting

confidence: 81%

“…For example, FOXD1 was found to be increased in prostate cancer tissues and associated with lymph node metastasis [9]. Another study has shown that FOXD1 promoted cell proliferation and chemotherapy resistance by inducing the G1 to S phase transition in breast cancer [10]. FOXD1 was reported to be significantly upregulated in glioma samples, and further investigations suggested that FOXD1 directly regulated ALDH1A3 transcription to activate clonogenic and tumorigenic potential of mesenchymal stem-like cells of glioma [8].…”

Section: Introductionmentioning

confidence: 97%

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FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

Fan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Forkhead box D1 (FOXD1) has a well-established role in early embryonic development and organogenesis and functions as an oncogene in several cancers. However, the clinical significance and biological roles of FOXD1 in non-small cell lung cancer (NSCLC) remain largely unknown. Methods: A total of 264 primary NSCLC tissue samples were collected. The expression levels of FOXD1 in these samples were examined by immunohistochemical staining. The expression of FOXD1 was knocked down by lentiviral shRNA. The relative expression of FOXD1 was determined by qRT-PCR, Western blotting and immunofluorescence image. The functional roles of FOXD1 in NSCLC were demonstrated cell viability CCK-8 assay, colony formation, cell invasion and migration assays, and cell apoptosis assay in vitro. In vivo mouse xenograft and metastasis models were used to assess tumorigenicity and metastatic ability. The Chi-square test was used to assess the correlation between FOXD1 expression and the clinicopathological characteristics. Survival curves were estimated by Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: We determined that higher levels of FOXD1 were present in NSCLC tissues, especially in metastatic NSCLC tissues. FOXD1 was also higher in all NSCLC cells compared with normal human bronchial epithelial cells. A higher expression level of FOXD1 was associated with malignant behavior and poor prognosis in NSCLC patients. Knockdown of FOXD1 significantly inhibited proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo, and it increased the apoptosis rates of NSCLC cells. Mechanistic analyses revealed that FOXD1 expressed its oncogenic characteristics through activating Vimentin in NSCLC. Multivariate Cox regression analysis indicated that FOXD1 was an independent prognostic factor both for overall survival (OS) and disease-free survival (DFS) in NSCLC patients. Conclusion: Our results indicated that FOXD1 might be involved in the development and progression of NSCLC as an oncogene, and thereby might be a potential therapeutic target for NSCLC patients.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 97%

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FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

Fan

et al. 2018

Cell Physiol Biochem

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“…However, Foxd1 has been implicated in several cancer types driven by aberrant Shh pathway signaling, including lung, breast, and prostate [34–37]. FOXD1 is overexpressed in lung, breast, and prostate cancer biopsies, and its depletion suppresses cell proliferation in lung and breast cancer cell lines [34,38,39]. Our finding that Shh drives Foxd1 expression in fibroblasts warrants further investigation into whether parallel regulation is operational in Shh pathway-driven cancer.…”

Section: Discussionmentioning

confidence: 80%

Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway

Fink

Sun

Heyne

et al. 2018

Cellular Signalling

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Sonic Hedgehog (Shh) signaling plays key regulatory roles in embryonic development and postnatal homeostasis and repair. Modulation of the Shh pathway is known to cause malformations and malignancies associated with dysregulated tissue growth. However, our understanding of the molecular mechanisms by which Shh regulates cellular proliferation is incomplete. Here, using mouse embryonic fibroblasts, we demonstrate that the Forkhead box gene Foxd1 is transcriptionally regulated by canonical Shh signaling and required for downstream proliferative activity. We show that Foxd1 deletion abrogates the proliferative response to SHH ligand while FOXD1 overexpression alone is sufficient to induce cellular proliferation. The proliferative response to both SHH ligand and FOXD1 overexpression was blocked by pharmacologic inhibition of cyclin-dependent kinase signaling. Time-course experiments revealed that Shh pathway activation of Foxd1 is followed by downregulation of Cdkn1c, which encodes a cyclin-dependent kinase inhibitor. Consistent with a direct transcriptional regulation mechanism, we found that FOXD1 reduces reporter activity of a Fox enhancer sequence in the second intron of Cdkn1c. Supporting the applicability of these findings to specific biological contexts, we show that Shh regulation of Foxd1 and Cdkn1c is recapitulated in cranial neural crest cells and provide evidence that this mechanism is operational during upper lip morphogenesis. These results reveal a novel Shh-Foxd1-Cdkn1c regulatory circuit that drives the mitogenic action of Shh signaling and may have broad implications in development and disease.

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“…Recent studies have suggested parallels between reprogramming and tumorigenesis, and highlighted the shared transcription factors involved. Similarly, the deregulation of FOXD1 is implicated in the tumorigenesis of cancers of prostate, breast, and clear cell sarcoma of the kidney (17–19). Nonetheless, the physiological roles of FOXD1 in brain cancers and GSCs remain unknown.…”

Section: Introductionmentioning

confidence: 99%

FOXD1–ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells

et al. 2016

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Glioma stem-like cells (GSC) with tumor initiating activity orchestrate the cellular hierarchy in glioblastoma (GBM) and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1-ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural (PN) GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Lastly, a novel small molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of GBM. Collectively, our findings define a FOXD1-ALDH1A3 pathway in controlling the clonogenic and tumorigenic potential of MES GSC in GBM tumors.

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FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27

Cited by 63 publications

References 29 publications

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway

FOXD1–ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells

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