BP1 Homeoprotein Enhances Metastatic Potential in ER-negative Breast Cancer

Fu, Yebo; Lian, Yi; Kim, Kyung Soon; Zhang, Lei; Hindle, Ashly; Brody, Fred; Siegel, Robert S.; McCaffrey, Timothy A.; Fu, Sidney W.

doi:10.7150/jca.1.54

Cited by 18 publications

(26 citation statements)

References 21 publications

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“…B and summarized in Table 1. Of 28 patients, 24 patients (85.7%) had detectable or high levels of DLX4 expression in breast tumors, consistent with previous reports 11, 17. 16 tumors (57.14%) exhibited detectable or high levels of both TWIST and DLX4 proteins, 2 tumors (7.14%) exhibited undetectable levels of both TWIST and DLX4 proteins, 3 tumors (10.7%) exhibited a relatively low DLX4 and high TWIST, 5 tumors (17.86%) exhibited a high level of DLX4 and an undetectable level of TWIST, 2 tumors (7%) exhibited undetectable DLX4 and high TWIST.…”

Section: Resultssupporting

confidence: 89%

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DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis

Zhang

Yang²,

Lin³

et al. 2012

Int. J. Biol. Sci.

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The distal-less homeobox gene 4 (DLX4) is a member of the DLX family of homeobox genes. Although absent from most normal adult tissues, DLX4 is widely expressed in leukemia, lung, breast, ovarian and prostate cancers. However the molecular targets, mechanisms and pathways that mediate the role of DLX4 in tumor metastasis are poorly understood. In this study, we found that DLX4 induces cancer cells to undergo epithelial to mesenchymal transition (EMT) through TWIST. Overexpression of DLX4 increased expression of TWIST expression in cancer cell lines, resulting in increased migratory and invasive capacity. Likewise, knocking down expression of DLX4 decreased TWIST expression and the migration ability of cancer cell lines. DLX4 bound to regulatory regions of the TWIST gene. Both western blotting and immunohistochemistry staining showed that the expression of DLX4 and TWIST are correlated in most of breast tumors. Taken together, these data from both cell models and tumor tissues demonstrate that DLX4 not only upregulates TWIST expression but also induces EMT and tumor metastasis. Altogether, we propose a new pathway in which DLX4 drives expression of TWIST to promote EMT, cancer migration, invasion and metastasis.

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Section: Resultssupporting

confidence: 89%

“…DLX4 gene expression is upregulated in 63% of AML cases including 81% of pediatric and 47% of adult cases, and in 32% of T-ALL 9 and in breast cancer 11. DLX4 controls many aspects of embryonic development, including bone morphogenesis, skeletal patterning and cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis

Zhang

Yang²,

Lin³

et al. 2012

Int. J. Biol. Sci.

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“…Since ER negative tumors are clinically more aggressive and have a poorer prognosis compared to ER positive tumors, the expression of BP1 might serve as a reliable marker of breast tumor aggressiveness 30. This was supported by our recent study demonstrating that BP1 enhances cell proliferation and metastatic potential in ER negative Hs578T breast cancer cells 31. Furthermore, the oncogenic properties of BP1 as revealed in the leukemia study suggest that the high percentage (80%) of BP1 expression in invasive ductal carcinomas contributes to enhanced breast tumor growth rate and invasiveness.…”

Section: Introductionsupporting

confidence: 65%

BP1, an Isoform of DLX4 Homeoprotein, Negatively Regulates BRCA1 in Sporadic Breast Cancer

Kluk¹,

Fu²,

Formolo³

et al. 2010

Int. J. Biol. Sci.

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Introduction: Several lines of evidence point to an important role for BP1, an isoform of DLX4 homeobox gene, in breast carcinogenesis and progression. BRCA1 is a well-known player in the etiology of breast cancer. While familial breast cancer is often marked by BRCA1 mutation and subsequent loss of heterozygosity, sporadic breast cancers exhibit reduced expression of wild type BRCA1, and loss of BRCA1 expression may result in tumor development and progression.Methods: The Cister algorithm and Genomatix program were used to identify potential BP1 binding sites in BRCA1 gene. Real-time PCR, Western blot and immunohistochemistry analysis were performed to verify the expression of BRCA1 and BP1 in cell lines and breast cancer tissues. Double-stranded siRNA transfection was carried out for silencing BP1 expression. ChIP and EMSA were used to confirm that BP1 specifically binds to BRCA1.Results: A putative BP1 binding site was identified in the first intron of BRCA1, which was confirmed by chromatin immunoprecipiation and electrophoresis mobility shift assay. BP1 and BRCA1 expression were inversely correlated in breast cancer cell lines and tissues, suggesting that BP1 may suppress BRCA1 transcription through consensus sequence binding.Conclusions: BP1 homeoprotein represses BRCA1 expression through direct binding to its first intron, which is consistent with a previous study which identified a novel transcriptional repressor element located more than 500 base pairs into the first intron of BRCA1, suggesting that the first intron plays an important role in the negative regulation of BRCA1. Although further functional studies are necessary to confirm its repressor activity towards BRCA1, the elucidation of the role of BP1 in breast tumorigenesis holds great promise in establishing BP1 as a novel target for drug therapy.

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“…Overexpression of BP1 was additionally shown to be present in lymph node metastasis in the immunohistochemistry analysis of inflammatory tumors, a rare but extremely aggressive form of breast cancer (24). Additional evidence found in breast cancer cell line models has implicated BP1 in the metastatic process (21,25). Interestingly, BP1 has been reported to play a critical role in epithelial–mesenchymal transition (EMT) (26,27) as well as in tumor resistance to several therapeutic agents (12,28,29)— mechanisms commonly associated with metastatic tumors.…”

mentioning

confidence: 92%

Increased copy number of the DLX4 homeobox gene in breast axillary lymph node metastasis

Torresan¹,

Oliveira²,

Pereira³

et al. 2014

Cancer Genetics

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DLX4 is a homeobox gene strongly implicated in breast tumor progression and invasion. Our main objective was to determine the DLX4 copy number status in sentinel lymph node (SLN) metastasis to assess its involvement in the initial stages of the axillary metastatic process. A total of 37 paired samples of SLN metastasis and primary breast tumors (PBT) were evaluated by fluorescence in situ hybridization, quantitative polymerase chain reaction and array comparative genomic hybridization assays. DLX4 increased copy number was observed in 21.6% of the PBT and 24.3% of the SLN metastasis; regression analysis demonstrated that the DLX4 alterations observed in the SLN metastasis were dependent on the ones in the PBT, indicating that they occur in the primary tumor cell populations and are maintained in the early axillary metastatic site. In addition, regression analysis demonstrated that DLX4 alterations (and other DLX and HOXB family members) occurred independently of the ones in the HER2/NEU gene, the main amplification driver on the 17q region. Additional studies evaluating DLX4 copy number in non-SLN axillary lymph nodes and/or distant breast cancer metastasis are necessary to determine if these alterations are carried on and maintained during more advanced stages of tumor progression and if could be used as a predictive marker for axillary involvement.

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BP1 Homeoprotein Enhances Metastatic Potential in ER-negative Breast Cancer

Cited by 18 publications

References 21 publications

DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis

DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis

BP1, an Isoform of DLX4 Homeoprotein, Negatively Regulates BRCA1 in Sporadic Breast Cancer

Increased copy number of the DLX4 homeobox gene in breast axillary lymph node metastasis

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