Molecular markers of epithelial-to-mesenchymal transition are associated with tumor aggressiveness in breast carcinoma.

BACKGROUND Epithelial-to-mesenchymal transition (EMT) is a transient process occurring during developmental stages and carcinogenesis, characterized by phenotypic and molecular alterations, resulting in increased invasive and metastatic capabilities of cancer cells and drug resistance. Moreover, emerging evidence suggests that EMT is associated with increased enrichment of cancer stem-like cells in neoplastic tissues. We interrogated the molecular alterations occurring in breast cancer using proposed EMT markers such as E-cadherin, vimentin, epidermal growth factor receptor (EGFR), platelet-derived growth factor (PDGF) D, and nuclear factor κ B (NF-κ B) to decipher their roles in the EMT and breast cancer progression. METHODS Fifty-seven invasive ductal adenocarcinomas of the breast were assessed for the expression of E-cadherin, vimentin, EGFR, NF-κ B, and PDGF-D using immunohistochemical analysis. Tumors were categorized into three groups: A (ER+, and/or PR+, HER-2/neu-), B (ER+, and/or PR+, HER-2/neu+), and C (triple-negative: ER-, PR-, and HER-2/neu-). Immunostained slides were microscopically evaluated and scored using intensity (0, 1+, 2+, and 3+) and percentage of positive cells, and data were statistically analyzed. RESULTS Membranous E-cadherin was positive in all 57 cases (100%), whereas cytoplasmic E-cadherin was predominantly positive in groups B and C compared with group A (21%, 7%, and 0%, respectively). All group A cases were negative for vimentin and EGFR. There was statistically significant increased expression of vimentin (P < .0002), EGFR (P < .0001), and NF-κ B (P < .02) in triple-negative cases when compared with groups A and B. CONCLUSIONS Vimentin, EGFR, and NF-κ B were significantly increased in triple-negative tumors, which is consistent with the aggressiveness of these tumors. These markers could be useful as markers for EMT in breast cancers and may serve as predictive markers for designing customized therapy in the future.

[1]  J. Inoue,et al.  Epigenetic alteration of the NF‐κB‐inducing kinase (NIK) gene is involved in enhanced NIK expression in basal‐like breast cancer , 2010, Cancer science.

[2]  Zhiwei Wang,et al.  Epithelial to Mesenchymal Transition Is Mechanistically Linked with Stem Cell Signatures in Prostate Cancer Cells , 2010, PloS one.

[3]  J. L. Costa,et al.  P-cadherin, vimentin and CK14 for identification of basal-like phenotype in breast carcinomas: an immunohistochemical study. , 2010, Histology and histopathology.

[4]  Zhiwei Wang,et al.  Emerging roles of PDGF-D signaling pathway in tumor development and progression. , 2010, Biochimica et biophysica acta.

[5]  Robin L. Jones,et al.  Beyond triple-negative breast cancer: the need to define new subtypes , 2010, Expert review of anticancer therapy.

[6]  W. Schulz,et al.  Snail regulates cell survival and inhibits cellular senescence in human metastatic prostate cancer cell lines , 2010, Cell Biology and Toxicology.

[7]  A. Bednarek,et al.  Does vimentin help to delineate the so-called 'basal type breast cancer'? , 2009, Journal of experimental & clinical cancer research : CR.

[8]  Zhiwei Wang,et al.  miR‐200 Regulates PDGF‐D‐Mediated Epithelial–Mesenchymal Transition, Adhesion, and Invasion of Prostate Cancer Cells , 2009, Stem cells.

[9]  Eric S. Lander,et al.  Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening , 2009, Cell.

[10]  M. Klymkowsky,et al.  Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. , 2009, The American journal of pathology.

[11]  Zhiwei Wang,et al.  Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. , 2009, Cancer research.

[12]  Zhiwei Wang,et al.  Plumbagin‐induced apoptosis of human breast cancer cells is mediated by inactivation of NF‐κB and Bcl‐2 , 2008, Journal of cellular biochemistry.

[13]  Zhiwei Wang,et al.  Platelet‐Derived Growth Factor‐D Overexpression Contributes to Epithelial‐Mesenchymal Transition of PC3 Prostate Cancer Cells , 2008, Stem cells.

[14]  A. Ben-Ze'ev,et al.  Epithelial-mesenchymal transition and the invasive potential of tumors. , 2008, Trends in molecular medicine.

[15]  Gema Moreno-Bueno,et al.  Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. , 2008, Cancer research.

[16]  Yiwei Li,et al.  Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy , 2007, Acta Pharmacologica Sinica.

[17]  M. Waltham,et al.  Vimentin and Epithelial-Mesenchymal Transition in Human Breast Cancer – Observations in vitro and in vivo , 2007, Cells Tissues Organs.

[18]  G. Sonenshein,et al.  Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2 , 2007, Nature Cell Biology.

[19]  Zhiwei Wang,et al.  Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model , 2006, Molecular Cancer Therapeutics.

[20]  A. Rajasekaran,et al.  Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. , 2006, Cancer research.

[21]  G. Prindull.  Hypothesis: cell plasticity, linking embryonal stem cells to adult stem cell reservoirs and metastatic cancer cells? , 2005, Experimental hematology.

[22]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[23]  Yiwei Li,et al.  Inactivation of NF-κB by genistein is mediated via Akt signaling pathway in breast cancer cells , 2003, Oncogene.

[24]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[25]  S. Ethier,et al.  Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. , 2001, Cancer research.

[26]  A. Leong,et al.  Co‐expression of cytokeratin and vimentin intermediate filament proteins in benign and neoplastic breast epithelium , 1989, The Journal of pathology.

[27]  Wei Chen,et al.  Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. , 2010, American journal of translational research.

[28]  Tadashi Kobayashi,et al.  EGFR as paradoxical predictor of chemosensitivity and outcome among triple-negative breast cancer. , 2009, Oncology reports.

[29]  Yiwei Li,et al.  NF-kappaB: a potential target for cancer chemoprevention and therapy. , 2008, Frontiers in bioscience : a journal and virtual library.

[30]  P. Maxwell,et al.  Vimentin expression does not assist in predicting survival in ductal carcinoma of the breast , 2002, Pathology.