title: BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion.
abstract: We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer.
authors.affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA. Electronic address: mcekanov@utk.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Cekanova
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Romaine I
authors.initials: RI
authors.lastname: Fernando
authors.affiliation: Department of Animal Science, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Nalin
authors.initials: N
authors.lastname: Siriwardhana
authors.affiliation: Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Sukhthankar
authors.affiliation: Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR, USA.
authors.forename: Columba de la
authors.initials: C
authors.lastname: Parra
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Jirayus
authors.initials: J
authors.lastname: Woraratphoka
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Malone
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Ström
authors.affiliation: Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Baek
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wade
authors.affiliation: Department of Animal Science, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Saxton
authors.affiliation: Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Donnell
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.affiliation: Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR, USA.
authors.forename: Suranganie
authors.initials: S
authors.lastname: Dharmawardhane
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN, USA. Electronic address: jwimalas@gmail.com.
authors.forename: Jay
authors.initials: J
authors.lastname: Wimalasena
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D061986:MCF-7 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C494819:BAD protein, human; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D051025:bcl-Associated Death Protein; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt
keywords: BAD; Breast cancer; Extracellular matrix invasion; Metastasis