Epithelial‐to‐Mesenchymal Transition Induced by TGF‐β1 Is Mediated by AP1‐Dependent EpCAM Expression in MCF‐7 Cells

The epithelial‐to‐mesenchymal transition (EMT), a process involving the breakdown of cell–cell junctions and loss of epithelial polarity, is closely related to cancer metastasis and invasion. The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane protein expressed in the majority of normal epithelial tissues and overexpressed in the majority of human epithelial cancers including breast cancer. EpCAM plays an important role in cancer progression. We showed that EpCAM participated in TGF‐β1‐induced EMT. TGF‐β1 treatment of MCF‐7 breast cancer cells was shown to induce EpCAM expression, which promoted the EMT and cell migration. EpCAM overexpression further enhanced TGF‐β1‐induced EMT and EpCAM knockdown inhibited TGF‐β1‐induced EMT. We further demonstrated that TGF‐β1 treatment induced the phosphorylation of JNK that was in turn responsible for the increased expression of Jun and Fos. This result suggests an important role of the JNK to AP‐1 signaling to EpCAM downstream of TGF‐β1 for the induction of EMT in the breast cancer cells. Collectively, our study highlights a novel function for EpCAM in TGF‐β1‐induced EMT process and suggests that targeting of EpCAM may be an attractive strategy to treat breast cancer. This study implicates the potential value of EpCAM as a molecular marker for breast cancer. J. Cell. Physiol. 230: 775–782, 2015. © 2014 Wiley Periodicals, Inc.

[1]  S. Krauss,et al.  The novel EpCAM-targeting monoclonal antibody 3–17I linked to saporin is highly cytotoxic after photochemical internalization in breast, pancreas and colon cancer cell lines , 2014, mAbs.

[2]  Semi Kim,et al.  TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion. , 2014, Cellular signalling.

[3]  W. Duan,et al.  Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. , 2013, The international journal of biochemistry & cell biology.

[4]  K. Dahlman-Wright,et al.  Expression of activator protein-1 (AP-1) family members in breast cancer , 2013, BMC Cancer.

[5]  I. Nilsson,et al.  EpCAM associates with endoplasmic reticulum aminopeptidase 2 (ERAP2) in breast cancer cells. , 2013, Biochemical and biophysical research communications.

[6]  P. Ram,et al.  Network Motifs in JNK Signaling. , 2013, Genes & cancer.

[7]  B. Giepmans,et al.  EpCAM: structure and function in health and disease. , 2013, Biochimica et biophysica acta.

[8]  Curtis J Henrich,et al.  High‐throughput Screening for Identification of Inhibitors of EpCAM‐Dependent Growth of Hepatocellular Carcinoma Cells , 2013, Chemical biology & drug design.

[9]  J. Rainer,et al.  EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth , 2013, Molecular Cancer.

[10]  María Liliana Franco-Chuaire,et al.  Epithelial-mesenchymal transition (EMT): principles and clinical impact in cancer therapy. , 2013, Investigacion clinica.

[11]  S. Dry,et al.  Epigenetic Activation of AP1 Promotes Squamous Cell Carcinoma Metastasis , 2013, Science Signaling.

[12]  A. Plückthun,et al.  Epithelial cell adhesion molecule-targeted drug delivery for cancer therapy , 2013, Expert opinion on drug delivery.

[13]  Dan Liu,et al.  Beta-Elemene Blocks Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7 through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors , 2013, PloS one.

[14]  Yu-lu Shi,et al.  Roles of p38 MAPK and JNK in TGF-β1-induced human alveolar epithelial to mesenchymal transition. , 2013, Archives of medical research.

[15]  I. Roxanis.  Occurrence and significance of epithelial-mesenchymal transition in breast cancer , 2013, Journal of Clinical Pathology.

[16]  H Putter,et al.  Expression of cell adhesion molecules and prognosis in breast cancer , 2013, The British journal of surgery.

[17]  Samy Lamouille,et al.  TGF-&bgr; signaling and epithelial–mesenchymal transition in cancer progression , 2013, Current opinion in oncology.

[18]  Hun-taeg Chung,et al.  Reactive oxygen species in the activation of MAP kinases. , 2013, Methods in enzymology.

[19]  G. Untergasser,et al.  Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines , 2012, BMC Cancer.

[20]  Jean Paul Thiery,et al.  Epithelial-mesenchymal transitions: insights from development , 2012, Development.

[21]  Ester Sánchez-Tilló,et al.  EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness , 2012, Cellular and Molecular Life Sciences.

[22]  C. Heldin,et al.  Regulation of EMT by TGFβ in cancer , 2012, FEBS letters.

[23]  Yong Li,et al.  Role of the EpCAM (CD326) in prostate cancer metastasis and progression , 2012, Cancer and Metastasis Reviews.

[24]  H. Mellstedt,et al.  Epithelial cell adhesion molecule expression (CD326) in cancer: a short review. , 2012, Cancer treatment reviews.

[25]  C. Tournier,et al.  Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. , 2012, Biochemical Society transactions.

[26]  O. Gires,et al.  EpCAM and its potential role in tumor-initiating cells , 2012, Cell adhesion & migration.

[27]  Y. Inoue,et al.  The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis , 2012, Breast Cancer.

[28]  T. Fleming,et al.  Activator protein 1 (AP-1) contributes to EpCAM-dependent breast cancer invasion , 2011, Breast Cancer Research.

[29]  L. Walsh,et al.  IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition , 2011, Cell Communication and Signaling.

[30]  S. Krobitsch,et al.  Effects of EpCAM overexpression on human breast cancer cell lines , 2011, BMC Cancer.

[31]  Anindita Dutta,et al.  Epigallocatechin-3-gallate (EGCG) downregulates gelatinase-B (MMP-9) by involvement of FAK/ERK/NFκB and AP-1 in the human breast cancer cell line MDA-MB-231 , 2010 .

[32]  A. Papavassiliou,et al.  Colon carcinogenesis: Learning from NF-kappaB and AP-1. , 2010, The international journal of biochemistry & cell biology.

[33]  E. Shaulian.  AP-1--The Jun proteins: Oncogenes or tumor suppressors in disguise? , 2010, Cellular signalling.

[34]  O. Gires,et al.  EpCAM as a target in cancer therapy. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Jiahuai Han,et al.  MAPK signaling in inflammation-associated cancer development , 2010, Protein & Cell.

[36]  Adrian V. Lee,et al.  Sustained c-Jun-NH2-Kinase Activity Promotes Epithelial-Mesenchymal Transition, Invasion, and Survival of Breast Cancer Cells by Regulating Extracellular Signal-Regulated Kinase Activation , 2010, Molecular Cancer Research.

[37]  Anindita Dutta,et al.  Epigallocatechin-3-gallate (EGCG) downregulates gelatinase-B (MMP-9) by involvement of FAK/ERK/NFkappaB and AP-1 in the human breast cancer cell line MDA-MB-231. , 2010, Anti-cancer drugs.

[38]  B. Ozanne,et al.  Transcription factors control invasion: AP-1 the first among equals , 2007, Oncogene.

[39]  Wen-Sheng Wu.  The signaling mechanism of ROS in tumor progression , 2007, Cancer and Metastasis Reviews.

[40]  J. Santibañez.  JNK mediates TGF‐β1‐induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes , 2006, FEBS letters.