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SUPPLEMENTAL DATA Table I. Biological Information for proteins over-abundant in cancerous breast tissue compared to adjacent benign tissue. (Listed in alphabetical order.) PROTEIN Aconitate hydratase, mitochondrial Actin, aortic smooth muscle (Alpha-actin-2) SECRETED/ FOUND IN BLOOD No Evidence No Evidence FUNCTION PREVIOUSLY FOUND IN CANCERS/ESPECIALLY BREAST Catalyzes interconversion of citrate to isocitrate in TCA cycle Major component of the contractile apparatus. Involved in cell structure & motility. Listed as critical protein in conversion to prostatic malignancy(1) Listed as one of 2 proteins able to help differentiate between borderline & malignant breast phyllodes. (2) Found to be up-regulated in proteomics study of membrane fractions from super-invasive cancer cells (This is a non-muscle actin) (3) Actin, cytoplasmic-1 (Beta-Actin) No Evidence A non-muscle cytoskeletal actin Adenine phosphoribosyltransferase No Evidence Catalyzes a salvage reaction that forms amp & is energetically less costly than de novo synthesis (deficiency causes 2,8dihydroxyadenine urolithiasis) Regulates phospholipase A2 activity. A calcium/phospholipids-binding protein that promotes membrane fusion & is involved in exocytosis. May have anti-inflammatory activity. Annexin A1 (Annexin I) (Lipocortin I) (Calpactin II) (Chromobindin-9) (p35) (Phospholipase A2 inhibitor) No Evidence Annexin A2 (Annexin II) (Lipocortin II) (Calpactin I heavy chain) (Chromobindin-8) Secreted Thought to cross-link plasma membrane phospholipids with actin and the cytoskeleton and be involved in exocytosis. 1 --Some gene & protein studies have shown upregulation in breast cancer & others downregulation (4,5) Expression may be involved in early stages of breast cancer development (6) Differentially expressed between chemoresistant and chemosensitive breast cancer cell lines (7) Previously shown to be over-expressed in breast cancer (8) Carbonyl reductase (NADPHdependent carbonyl reductase 1) No Evidence Catalyzes the reduction of several carbonyl compounds including the antitumor anthracycline antibiotics. Converts prostaglandin e2 to prostaglandin f2-alpha Listed in numerous articles related to SERMs, but specific form of carbonyl reductase often not defined. Cathepsin D [Contains: Cathepsin D light chain; Cathepsin D heavy chain] Cellular retinoic acid-binding protein 2 (Cellular retinoic acidbinding protein II) No Evidence Acid protease involved in intracellular protein breakdown, cell invasion, apoptosis Has been/is being widely studied as a biomarker of breast cancer (9,10) No Evidence Induces cell differentiation and may antagonize cancer progression. May regulate the access of retinoic acid to the nuclear retinoic acid receptors to help control differentiation. Coactosin-like protein No Evidence Chloride intracellular channel protein 1 (Nuclear chloride ion channel 27) No Evidence Elongation Factor Tu, mitochondrial (EF 1 alpha1);(Prostate tumor-inducing protein-1) No Evidence A calcium-dependent F-actin binding protein that helps regulate the actin cytoskeleton. Localizes mostly to cell nucleus but has both nuclear & plasma membrane chloride ion channel activity. Stabilizes cell membrane potential, maintains intracellular pH & cell volume, & participates in transport. Aids in gtp-dependent binding of aminoacyltRNA to ribosomes (a-site) during protein synthesis Some genetic studies show that CRBP downregulation may contribute to breast tumor progression (11) Others have shown that the CRBP gene is expressed predominantly in ER+ breast cancer cell lines (12) Antibodies to this protein have been reported in the serum of pancreatic cancer patients (13) Has been listed as an important protein in the early phase of mammary carcinogenesis in a study of cell lines (14) 2 --- Fibrinogen beta chain [Contains: Fibrinopeptide B] Yes, blood-borne glycoprotein Aids in platelet aggregation (i.e. is a cofactor) Flavin reductase (NADPHdependent diaphorase) No Evidence Fructose-bisphosphate aldolase A (Muscle-type aldolase) (Lung cancer antigen) The gene has been detected in the serum of lung cancer patients. (17) RNA/DNA corresponding to this protein has been found in serum (18,19) Involved in electron transfer from pyridine nucleotides to flavins; protects cells from oxidative damage Glycolytic enzyme Glyceraldehyde-3-phosphate dehydrogenase Heat Shock 70kDa protein 5 (glucose-regulated protein, 78kDa) Autoantibodies against this protein, have been found in the serum of prostate cancer patients (21) 3 Up-regulated in malignant pleural effusions (15) In breast cancer fibrinogen is deposited but not converted to fibrin in the tumor stroma. (16) --- --Catalyzes a step in carbohydrate metabolism – oxidative phosphorylation of glyceraldehyde-3-phosphate Aids in the assembly of multimeric protein complexes inside the ER Has been associated w/cancers previously. Increased glycolysis in cancer cells may be associated with tumor invasion & metastasis (20) Often the gene measured to quantify cell-free plasma DNA in cancer patients (18) This protein has been related to: colon cancer (22), neuroblastic tumors (23), and prostate cancer (21). The gene has been linked to breast cancer (24). Isocitrate dehydrogenase, cytoplasmic (soluble) Currently being investigated as a serum marker for TB (25) Plays a role in cytoplasmic NADPH production Protein previously found to be upregulated in breast tumor cells (26) Isocitrate dehydrogenase 2 (NADP), mitochondrial No evidence Studies from the 1970’s showed associations with breast cancer– particularly with response to treatment (27). Keratin 7 (sarcolectin) Found in sera of HIV-postive patients (28). Is involved with intermediary metabolism & energy production. May associate with pyruvate dehydrogenase complex. Proteins arranged in pairs during differentiation of simple and stratified epithelial tissues Keratin, type I cytoskeletal 19 (Cytokeratin-19) A fragment of cytokeratin 19 (CYFRA21-1) has been shown to decrease during chemotherapy in pt’s with NSCLC (30). Expression of the Keratin 19 gene has been associated with more aggressive breast cancers (31). --- 4 Previously found to be over-expressed in breast cancer (29). Keratin, type II cytoskeletal 8 (Cytokeratin-8) (Keratin-8) Autoantibodies to CK-8 have been detected in serum (32). --- Leukocyte elastase inhibitor (serpin B1); (Monocyte/neutrophil elastase inhibitor) Has been found in BALF – is also on the surface of neutrophils (37) Regulates activity of the neutrophil proteases: elastase, cathepsin, and proteinase-3 Lumican Yes Malate dehydrogenase, mitochondrial No Evidence May organize collagen fibrils and circumferential growth, corneal transparency, and epithelial cell migration & tissue repair Plays a role in the malateaspartate shuttle that operates in the metabolic coordination between cytosol & mitochondria 5 Some studies found suppression of CK-8 in tumors compared to normal mammary epithelia or fibroadenomas (33,34). Another found that CK-8 was expressed in breast tumor cells while CK-17 and vimentin expression was lost (35). Yet another found that expression of the CK-8 gene was low in tumors w/BRCA1 mutations & high in tumors w/BRCA2 mutations – described for ER+ sporadic tumors of luminal origin (36). Several cancer cell lines, including breast cancer produce this protein and the amount is related to prognostic indicators (38). Previous proteomics studies have found lumican to be overexpressed in breast tumor tissue compared to normal breast tissue (39,40) Older studies show increased activity of malate dehydrogenase in cancer but do not always specify the form of malate dehydrogenase (41). Myosin light polypeptide 6 (Myosin light chain alkali 3) (Myosin light chain 3) No Evidence This is the non-muscle and smooth muscle variant of myosin light chain 6. Peptidyl-prolyl cis-trans isomerase B (PPIase) (Rotamase) (Cyclophilin B) Phosphatidylethanolami ne-binding protein 1 (PEBP-1) (Prostaticbinding protein) Yes Accelerates the folding of proteins Phosphoglycerate mutase 1 Found in blood in an anaerobic exercise study (44) Catalyzes reaction of 3phosphoglycerate to 2phosphoglycerate in the glycolytic pathway. 14 kDa phosphohistidine phosphatase (phosphohistidine phosphatase 1) 14-3-3 protein epsilon (14-3-3E Tyrosine 3monooxygenase Proteasome activator complex subunit 1 (Proteasome activator 28-alpha subunit) No Evidence Regulates somatic sex differentiation One study (attempting to look at the relationship between alcohol and BC) found that BC cell lines overexpressed this gene and that this upregulation was further stimulated by ethanol (42). Has been implicated with prolactin in the cell signaling of breast cancer (43) No Evidence _ _ One study found over-expression of this enzyme in cancerous breast tissue compared to normal breast tissue. (45) --- No Evidence Mediates signal transduction by binding to phosphoserine containing proteins No Evidence Cleaves peptides (one of three subunits – alpha, beta, gamma). Required for efficient antigen processing & immunoproteasome assembly 6 Found to be over-expressed in a metastatic breast cancer cell line vs. a non-metastatic cell line (46) --- Protein DJ-1 (Oncogene DJ1) (Parkinson disease protein 7) Found in serum of Parkinson’s Disease patients & controls (47,48) PDJ1 is a positive regulator of androgen receptor-dependent transcription. May regulate PTEN, a tumor suppressor. Both DJ-1 and PTEN are negatively correlated in primary breast cancer samples (49) Rho GDP-dissociation inhibitor 1 (Rho-GDI alpha) No Evidence Involved in the regulation of the gdp/gtp exchange reaction of rho proteins – inhibits dissociation of gdp & binding of gtp Interacts directly with DNA-bound ER alpha to influence ER signaling (50). Has been associated with a higher rate of metastasis in one study of cell lines (51) S-Formylglutathione hydrolase Also called Esterase D Septin 11 No Evidence The gene has been studied extensively in retinoblastoma No Evidence Potential role in cytokinesis Most cancer references for this protein refer to over-expression in retinoblastoma (52) --- SH3 domain-binding glutamic acid-rich-like protein Transitional ER ATPase or Valosin-containing protein No Evidence Plays a role in protein-protein interactions in signal transduction pathways Fragments golgi stacks during mitosis and reassembles them after mitosis No Evidence 7 Has been found to be up-regulated in glioblastoma multiform versus non-tumor brain tissues (53) The gene corresponding to this protein was amongst 5 genes that were under-expressed in the tumors of women who died within 5 years after surgery for removal of a cancerous breast tumor. (54) Tropomyosin alpha-4 chain (Tropomyosin-4) (TM30p1) No Evidence Tubulin beta-5 chain (Beta-tubulin isotype I) No Evidence Vimentin The endothelial cell-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature (58) Binds actin filaments in muscle & non-muscle cells. Associates w/troponin complex. In non-muscle cells stabilizes cytoskeleton actin filaments Main component of microtubules. Note: Taxanes inhibit microtubule function by stabilizing GDP-bound tubulin Cytoskeletal element (along w/actins & tubulins) that shows mesenchymal specific expression. 8 One study found tropomyosin 4 to be among 9 proteins (2 of the others were beta 5-tubulin & vimentin) that were over-expressed in infiltrating ductal carcinoma compared to adjacent normal tissue (55) Relationship between Class I beta tubulin (and gene) and the resistance of breast cancers to docetaxel has been studied with mixed results (56,57) Listed among a group of proteins able to help differentiate between borderline & malignant breast phyllodes (2) Table II. Biological Information for proteins less abundant in cancerous breast tissue compared to adjacent benign tissue. Proteins are listed in alphabetical order. PROTEIN SECRETED FUNCTION FOUND IN CANCERS/ESPECIALLY BREAST Alpha-1-Antichymotrypsin Identified as a secreted biomakers of breast cancer. (59) Plasma protease inhibitor – deficiency indicative of liver/lung disease Alpha-1-antitrypsin (Alpha-1 protease inhibitor) (Alpha-1antiproteinase) Identified as a secreted biomakers of breast cancer. (59) Inhibitor of serine proteases, primary target is elastase. Most studies of breast cancer found this protein to be higher in disease (60,59). However, this protein binds to PSA. A lower proportion of free:bound psa is a good prognostic indicator in some cancers (61). Some studies have found an increase in breast cancer (59) Other studies have found this protein to be decreased in breast cancer (10) Alpha-2-HS-glycoprotein (fetuin A) Yes Involved in endocytosis, brain development, formation of bone tissue. Present in bone marrow hemopoietic matrix. Molecular calcium binding chaperonepromotes folding & oligomeric assembly in the ER via the calreticulin/calnexin cycle Stores iron in readily available, non-toxic form Calreticulin Yes Ferritin heavy chain (Ferritin H subunit) (Proliferation-inducing gene 15 protein) Yes Ig gamma-1 chain C region Yes --- Immunoglobulin J chain Yes Links two monomer units of either IgM or IgA, also links these units to secretory component 9 --- --- Serum ferritin has been shown to be increased in patients with breast cancer (62) Previously shown to be decreased in infiltrating ductal carcinoma in situ (63) --- Programmed cell death protein 6 (Probable calcium-binding protein ALG-2) Not listed Serotransferrin (Transferrin) (Siderophilin) (Beta-1-metal-binding globulin) Yes Calcium binding protein required for Tcell receptor, -Fas, and glucocoritcoid-induced cell death Transports iron from sites of absorption and heme degradation to those of storage/utilization. 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