Expression of epithelial-mesenchymal transition–related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome

Jang, Min Hye; Kim, Hyun Jeong; Kim, Eun Joo; Chung, Yul Ri; Park, So Yeon

doi:10.1016/j.humpath.2015.05.010

Cited by 128 publications

(113 citation statements)

References 35 publications

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“…The role of m-CD24 in cancer progression seems complicated with some studies show promotion role [58, 59], while others associate c-CD24 instead with cancer progression [7, 60–62]. The current studies IRISOE-induced accumulation of c-CD24 association with increased aggressiveness in TNBCs in animal models [38] and humans (this study) are consistent with previous studies.…”

Section: Discussionsupporting

confidence: 89%

“…Closely associated with the induction of the basal phenotype in TNBCs is the acquisition of epithelial-to-mesenchymal transition (EMT), which is most likely involved in their initial steps of invasion and metastasis [6, 7], and drug resistance [8]. TNBCs clinical and pathologic features overlap with hereditary BRCA1 related breast cancers [9].…”

Section: Introductionmentioning

confidence: 99%

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BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

et al. 2016

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Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

et al. 2016

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“…Furthermore, the expression profiles of ZEB1 and ZEB2 are inversely correlated with those of ESRPs in human breast cancer cell lines and tumor specimens (Horiguchi et al ., 2012). Consistent with the relationships between the EMT and cancer malignancy, high expression of ZEB1 is associated with poor prognosis of many types of cancer, including breast cancer (Chu et al ., 2013; Jang et al ., 2015). ZEB2 expression is also reported to be associated with poor prognosis of several types of cancer, although less frequently than ZEB1 (Fang et al ., 2013; Prislei et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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“…Breast cancer is a heterogeneous and complex genetic disease with different molecular bases. Despite recent advances in early detection and multimodality therapies, triple-negative breast cancers (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers show aggressive behaviors and poor clinical outcomes [2 3 4]. For this reason, the identification of new biomarkers that are associated with potential therapeutic agents and prognostic markers is clinically important.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer

Lee

Bae

et al. 2017

J Breast Cancer

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PurposeTransducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. We investigated the prognostic significance of TLE1 protein expression in breast cancers by using immunohistochemistry and explored the relationship of TLE1 with clinicopathological parameters.MethodsImmunohistochemistry was performed on 456 cases of breast cancer tiled on tissue microarrays. The relationship between TLE1 expression in normal breast specimens and ductal carcinoma in situ (DCIS) was also analyzed.ResultsTLE1 was highly expressed in 57 of 456 (12.5%) carcinoma samples. TLE1 was more frequently expressed in DCIS and invasive breast cancers than in normal breast tissue (p=0.002). High expression of TLE1 significantly correlated with negative lymph node (LN) metastasis (p=0.007), high histologic grade (p<0.001), estrogen receptor negativity (p<0.001), progesterone receptor negativity (p<0.001), human epidermal growth factor receptor 2 (HER2) positivity (p<0.001), and high Ki-67 proliferation index (p<0.001). Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease-free survival (DFS) (p=0.167) or overall survival (OS) (p=0.286). In subgroup analyses, no correlation was found between TLE1 expression and DFS or OS according to LN status or intrinsic subtype.ConclusionHigh TLE1 expression is significantly associated with the HER2+ and TNBC subtypes. This is the first study documenting immunohistochemical expression of TLE1 in invasive breast cancer and its association with clinicopathological parameters, prognosis, and intrinsic subtype.

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Expression of epithelial-mesenchymal transition–related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome

Cited by 128 publications

References 35 publications

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer

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