J. Our findings indicate the need for a reappraisal of the role of the decoy receptors in cancer pathogenesis. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Pathway Signaling. Tumors were obtained from primary lung cancers resected at M.D Anderson Cancer Center (Houston, TX). 4, Representative examples of methylation specific PCR for DcR1 and DcR2 in breast (BrT), lung (LuT), mesothelioma (MST), bladder (BlT), prostate (PrT), lymphoma (Ly), leukemia (Le), multiple myeloma (MM), cervix (Cx) tumors and nonmalignant samples. The concordance between loss of gene expression and aberrant methylation was 73% for breast and 100% for both lung cancer and MM cell lines (Fig. MMs were obtained from patients resected by Dr. Harvey Pass at the National Cancer Institute (Bethesda, MD). Thus, based on the current knowledge, DcR1 or DcR2 are believed to inhibit apoptosis induction mediated through DR4 and DR5.5. ↵1 This work was supported by funding from the Korea Research Foundation made in the program year of 1998 (F-05) and from the Catholic Medical Center of Korea (the special project of 1999). Reverse transcription (RT) reaction was carried out on 2 μg total RNA with the SuperScript II First‐Strand Synthesis using oligo (dT) primer System (Life Technologies Rockville, MD). B, tumor cell glands were dissected, leaving large holes behind. In all such cases the corresponding tumors were methylated. Thus, we are still left to explain how silencing of decoy receptors could favor tumorigenesis. Amplification of the desired PCR product for each gene was initially confirmed through direct sequencing of the PCR product as described previously.16 The house keeping gene GAPDH was used as an internal control to confirm the success of the RT reaction. 3, Positive control, methylated cell line DNA confirmed through sequencing. (25 . Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy. DcR1 transcripts … This observation suggests that methylation may commence before tumor formation and may represent a field effect. Chemopreventive agent-induced modulation of death receptors. 6, We also examined the methylation status of TRAIL receptor genes in many other types of malignancies. Methylation of DR4 and DR5 was rare in all the tumor types examined. Each PCR reaction was performed under standard conditions in a 10-μl reaction mixture containing 1 μl of template DNA, 0.5 μm of each primer, 0.2 μm of each deoxynucleotide triphosphate, 1.5 mm MgCl2, 0.4 units of Taq polymerase, 0.5 μCi of [32P]dCTP (Amersham, Buckinghamshire, United Kingdom), and 1 μl of 10× buffer. Acta Haematologica, 2005. Cell lines were initiated by AFG (breast, lung, some MMs) or HIP (most MMs).21, 22, 23 Twenty‐seven lung cancer cell lines and 23 breast cancer cell lines and were grown in RPMI‐1640 medium (Life Technologies Inc., Rockville, MD) supplemented with 5% FBS and incubated in 5% CO2 at 37°C. Hypermethylation of DcR1, DcR2, DR4, DR5 gene promoters and clinical significance in tongue carcinoma. Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study. , 26) The majority of the mutations (10 of 11) were detected in exon 9, which encodes the death domain region of TRAIL-R2 2E) Representative SSCPs show “not informative”(left), “retention of heterozygosity” (middle), and LOH (right). Cancer Res. Interleukin 1β and Prostaglandin E2 affect expression of DNA methylating and demethylating enzymes in human gingival fibroblasts. (5) Binding of TRAIL to TRAIL-R2 induces trimerization of TRAIL-R2, and FADD/MORT-1 binds to the trimerized TRAIL-R2 cytoplasmic region (death domain; Ref. The rhTRAIL (Dulanermin), Mapatumumab (HGS-ETR1), Tigatuzumab (CS-1008), Lexatumumab (HGS-ETR2), Drozitumab (PRO95780), Conatumumab (AMG-655), LBY-135 and Apomab have already been tested in clinical trials [6,7,29,30].Mapatumumab had the most promising outcome … DR4 mRNA was detected in JAR, JEG-3, BeWo and HTR-8/SVneo cells, whereas DR5 was present in all detected cells. 3). Epigenetic regulation of cell life and death decisions and deregulation in cancer. Archives of Pathology & Laboratory Medicine. 7, Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. . Clearly therefore, studies are now needed that attempt to find another gene alterations at this region, including TRAIL-R1. In our study, seven TRAIL-R2 gene mutations seemed to be hemizygous mutations without allelic deletion (Table 1) The splice-site mutation affected position −1 of the consensus sequence of the acceptor splice site of intron 8. We further examined the role of clathrin pathway in TRAIL receptor endocytosis by targeted gene silencing. Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of … TRAIL-induced apoptosis can be blocked by several mechanisms, including the expression of decoy receptors for TRAIL The adapter molecule FADD recruits caspase-8 to the activated receptor. TRAIL-R1 and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL). . Aberrant methylation frequency of TNFRSF10C Promoter in pancreatic cancer cell lines. Whether TRAIL-R2 is such a tumor suppressor is unknown at this time, but its function as a death receptor would be consistent with the tumor suppressor function. It is possible that in lung and breast cancers we may not have statistically adequate number of cases in different stages to arrive at such a conclusion. The frequencies of methylation in breast tumors and MMs were higher than that reported previously for neuroblastomas (∼25–30%).20 Comparable frequencies of methylation were observed in lung tumors. Cancer Research Print ISSN: 0008-5472 Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. In breast and lung cancers, there were no differences between methylation positive and negative groups in respect to gender, age and stage (data not shown). NIMA-Related Protein Kinase 1 Is Involved Early in the Ionizing Radiation-Induced DNA Damage Response, Crucial Role of Phospholipase Cε in Chemical Carcinogen-Induced Skin Tumor Development, Cancer Epidemiology, Biomarkers & Prevention, Alterations of the DR5/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers. Our data indicate that somatic mutation of TRAIL-R2 may play a role in the pathogenesis of some NSCLCs and that the TRAIL-R2 gene is one of the genes relevant to the frequent loss of chromosome 8p21-22 in NSCLC. Three breast cancer cell lines (HCC1395, HCC2218 and HCC1954), 3 lung cancer cell lines (NCI‐H2171, NCI‐H82 and NCI‐H2227) and 3 MM cell lines (NCI‐H290, NCI‐H2052 and NCI‐H2452) that showed loss of expression and presence of methylation by MSP for both DcR1 and DcR2 were cultured with 5‐aza 2′‐deoxycytidine (5‐Aza‐CdR) (4 μM, 6 days). Based on our previous findings of loss of expression data for DR4 (non‐small cell lung cancer, 10%; small cell lung cancer, 20%) and DR5 (non‐small cell lung cancer, 35%; small cell lung cancer, 50%) in lung cancer cell lines19 there was no significant concordance between methylation and loss of gene expression. Overall, 11 tumors (10.6%) were found to have TRAIL-R2 gene mutations in the death domain known to be involved in the transduction of an apoptotic signal. (4) Water blanks were included with each assay. ⇓ TRAIL receptor DR4 was highly expressed in THP-1 & LPS-primed primary monocytes but not in the non-primed primary monocytes. In the 13 tumor types examined one or both genes were methylated in 19–100% of all tumor types. , 10) (21) ⇓ (2, , 10 The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis (PubMed:19090789). For all tests, probability values of p < 0.05 were regarded as statistically significant. Overcoming TRAIL resistance in ovarian carcinoma. . NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. The nonsense mutation showed a point mutation introducing premature termination signal at codon 354 (Fig. PCR products were analyzed on 2% agarose gels. Methylation data are presented below and summarized in Table I. Aberrant methylation of DcR1 was found in 11 of 23 (48%) breast cancer cell lines, in 10 of 27 (37%) lung cancer cell lines and in 3 of 7 (43%) MM cell lines (Table I, Fig. DNA methylation profile of 28 potential marker loci in malignant mesothelioma. Methylation of the 2 decoy receptors, however, occurred independently of each other and of DR4 and DR5 (which were infrequently methylated in the tumor types we examined). Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. The extracellular domains of DcR1 or DcR2 compete with those of DR4 or DR5 for TRAIL binding. (20) The clinicopathological stage was determined after surgery using standard criteria. , and cases 24 and 42 showed only aberrant bands of the mutant allele without those of the wild-type allele on SSCP of exon 9 (Fig. (3) Genes 0 Matches; ... APOPTOSIS INDUCING RECEPTOR TRAIL-R2 wasn't a match in our system. DNA Methylation and Apoptosis Resistance in Cancer Cells. Positive control, RNA from normal lung; negative control, water blank. Expression of the house keeping gene GAPDH was run as a control for RNA integrity. (GenBank accession no. Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG (PubMed:26457518, PubMed:10549288). 2 The other tumors were obtained from UT Southwestern Medical Center (Dallas, TX). Analysis of data pertaining to expression of decoy receptors and TRAIL sensitivity (in terms of % survival) showed a mean survival of 12% for 2 lines lacking expression of both receptors, 21% for 2 cell lines lacking DcR1 expression and 50% for a cell line expressing both receptors (Table II). Aberrant methylation was absent in normal and non malignant specimens corresponding to all these tumor types examined. Identification of Novel Methylation Markers in Hepatocellular Carcinoma using a Methylation Array. (22 The TRAIL-R2 gene recently has been mapped to chromosome 8p21-22. In MM aberrant methylation was predominantly limited to the epithelial type and was rare in the sarcomatous or mixed types. Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. For methylated cell lines the loss of DcR1 was found in 8 of 11 (73%) breast cancer cell lines, in 10 of 10 (100%) lung cancer cell lines and in 3 of 3 (100%) MM cell lines. Tanvira Afroze. TRAIL resistance is known to be mediated by several mechanisms Therefore, the demonstration of TRAIL-R2 gene mutations in NSCLCs in this study suggest that TRAIL-R2 may be one of the tumor suppressor genes at chromosome 8p21-22 and that TRAIL-R2 gene mutations are involved in the development of NSCLCs. In the case of prostate cancer methylation of either DcR1 or DcR2 was correlated with improved prognosis (p = 0.03). In tumor and nonmalignant samples, most of which consist of mixtures of tumor cells and non‐malignant cells, either the unmethylated band only or both methylated and unmethylated bands were present. Aberrant methylation of DcR2 was found in 25 of 40 (63%) breast cancers, 15 of 62 (24%) lung cancer and 26 of 66 (39%) primary MMs. ), SSCP analysis at these polymorphic sites was used for the detection of LOH as well as for the detection of mutations. ↵4 The abbreviations used are: TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRAIL-R1 and -R2, TRAIL receptor-1 and -2; NSCLC, non-small cell lung cancer; SSCP, single-strand conformational polymorphism; LOH, loss of heterozygosity. (11) , 13) Adenovirus-mediated IKKβKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. , 23) Gene methylation in pleural mesothelioma: Correlations with clinico-pathological features and patient's follow-up. APOPTOSIS INDUCING RECEPTOR TRAIL-R2 wasn't a match in our system. These receptors were found to be widely expressed in normal and neoplastic cells Enter multiple addresses on separate lines or separate them with commas. (10) Blockade of TRAIL-induced apoptosis may lead to the loss of its apoptotic function and prolong the survival of affected cells. Copy number profiling in von hippel‐lindau disease renal cell carcinoma. The 4 TRAIL receptors are located in tandem fashion at chromosome location 8p21‐22.3, 25, 26 Methylation is known to initiate at one or more chromosomal CpG sites in a promoter region and spread to adjacent sites along the DNA strand until it meets a counteracting force in the form of open and active chromatin.27 Methylation (and resultant silencing) of the proapoptotic DR4 and DR5 receptor genes may result in silencing of the adjacent DcR1 and DcR2 receptors genes. . TRAIL harbors potential as a cancer therapeutic agent because it has been known to efficiently kill many tumor cell lines but not normal cells Total RNA was extracted from the cell lines with Trizol (Life Technologies, Rockville, MD) following the manufacturer's instructions. Several candidate tumor suppressor genes of this region have been identified of TRAIL. 17, (11) Thus it is possible that methylation of the DcR1 and DcR2 receptor genes may represent a secondary effect of no clinical importance. Genomic DNA was obtained from cell lines, primary tumors and non‐malignant cells by digestion with proteinase K (Life Technologies), followed by phenol/chloroform (1:1) extraction and ethanol precipitation. Cancer diagnostic classifiers based on quantitative DNA methylation. AB014710-8; Ref. . Thus, in cell lines in which all other key components of DISC are expressed, loss of decoy receptors appear to enhance the pro‐apoptotic effect. . Clinicopathological data were available for lung cancer, breast cancer, MM and prostate cancer. 2, A and C) . Apoptosis resistance and response to chemotherapy in primary nodal diffuse large B‐cell lymphoma. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. . Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression. . DNA methylation changes in ovarian cancer: Implications for early diagnosis, prognosis and treatment. . ⇓ Its expression, like the other three TRAIL receptors (i.e., DR4, DR5, and DcR1), is regulated by p53. These data strongly indicate that chromosome 8p21-22 may harbor one or more tumor suppressor genes and suggest that the TRAIL-R2 gene might be one of the candidate tumor suppressor genes in this region. 2, . 1) 21 The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. ; Fig. ). Impact of DNA methyltransferases on the epigenetic regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in malignant melanoma. . Additionally, gene therapy approaches using TRAIL-encoding adenovirus (Ad-TRAIL) are currently being developed to overcome the limitations inherent to TRAIL receptor targeting, i.e., pharmacokinetic of soluble TRAIL, pattern of receptor expression, and tumor cell resistance. TRAIL R3/DcR1, R4/DcR2 and soluble decoy osteoprotegerin are truncated without a ‘death domain’, prevent cell apoptosis,2 but may result in non-canonical signalling through the receptor-interacting serine/threonine-protein kinase 1, TNF receptor-associated factor 2 and inhibitor of NF-κ subunit gamma.4 Genetic variation in the TNFSF10 gene has been associated with asthma, but … Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. The TRAIL-R2 gene was mapped to chromosome 8p21-22 ], Sign In to Email Alerts with your Email Address. About this Attention Score Average Attention Score compared to outputs of the same age. TRAIL is known to bind to 4 different receptors, 2 proapoptotic ( DR4 and DR5 ), and 2 potentially antiapoptotic receptors lacking death domains ( DcR1 and DcR2 ). This can reflect the presence of inhibiting mechanisms of TRAIL-induced apoptosis. (10) BrP3, nonmalignant breast tissue corresponding to BrT1. (21) Malignant cells were selectively procured from H&E-stained slides without any contamination by normal cells, using a 30G1/2 hypodermic needle (Becton Dickinson, Franklin Lakes, NJ) affixed to a micromanipulator, as described previously ⇓ Aberrant methylation of DcR2 was found in 17 of 23 (74%) breast cancer in 13 of 27 (48%) lung cancer and in 5 of 7 (71%) MM cell lines (Table I, Fig. Treatment with 5‐aza‐2′‐deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. In contrast, cases 40 and 44 showed LOH at one of the intragenic polymorphic sites (Table 1) Decoy receptor 1 (DCR1), also known as TRAIL receptor 3 (TRAILR3) and tumor necrosis factor receptor superfamily member 10C (TNFRSF10C), is a human cell surface receptor of the TNF-receptor superfamily. All statistical tests were 2‐sided. New Diagnostic and Molecular Characteristics of Malignant Mesothelioma. Florent Dufour INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. Use the link below to share a full-text version of this article with your friends and colleagues. Epigenetic Biomarkers in the Management of Ovarian Cancer: Current Prospectives. 9) Epigenetic modifications in prostate cancer. D, sequencing analysis from aberrant band of case 42. Number of times cited according to CrossRef: TRAIL receptor signaling: From the basics of canonical signal transduction toward its entanglement with ER stress and the unfolded protein response. . Advances in the biology of malignant pleural mesothelioma. . ⇓ As shown in Fig. Gene Name: TNFRSF10B. 4 A, part of exon 9 was amplified. ⇓ In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. None of the corresponding normal samples showed evidence of mutations by SSCP (Fig. A, malignant cells are arranged in irregularly shaped glands in the lung tissue. Primer sequences and conditions for RT‐PCR product were described previously20 and confirmed that genomic DNA was not amplified with these primers. To date, TRAIL-R2 gene mutations have been reported in two cases of head and neck cancer, and these mutations were detected in exon 9, which encodes for death domain (1997) demonstrated that DCR2 (), a second TRAIL decoy receptor, is also located at 8p21, suggesting that the TRAIL receptor genes arose by recent gene duplication events. Increased sensitivity to TRAIL in cell lines and increased survival of MM and prostate cancer patients with loss of gene expression or methylation support this concept. Mutations and deletions of the TRAIL-R2 gene in NSCLCs. TRAIL induces monocyte migration mediated by TRAIL receptor DR4 via the RhoGTPase signaling pathway. (26) CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. The role of the TRAIL receptors in cancer cells appears to be more complex than was originally thought and the various receptors may have dual pro and anti cell survival effects. , studies on the underlying mechanisms of the TRAIL resistance in cancer has been required. Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression. . In breast and lung cancers there were no differences between methylation positive and negative groups in respect to gender, age and stage (data not shown). Original magnification, ×100. Tumor-derived Mutations in the TRAIL Receptor DR5 Inhibit TRAIL Signaling through the DR4 Receptor by Competing for Ligand Binding. In MMs DcR2 methylation was correlated with improved prognosis (p = 0.04). The genes for the four TRAIL receptors are tightly clustered on human chromosome 8p21–22 [46–48], suggesting they evolved relatively recently via gene duplication. and you may need to create a new Wiley Online Library account. CpG Island Hypermethylation in Breast Cancer Progression and Metastasis. Amplification of the desired PCR product for each gene was initially confirmed through direct sequencing of the PCR product as described previously.16 Briefly, for MSP analysis 1 μg of genomic DNA was denatured by NaOH and modified by bisulfite. Table I also shows data pertaining to the analysis of methylation of TRAIL receptors in various other tumor types. Developmental DNA methyltransferase inhibitors in the treatment of gynecologic cancers. Representative examples of methylation specific PCR for DcR1 (a, upper panels) for DcR2 (a, lower panels) in cancer cell lines. The concordance between loss of gene expression and aberrant methylation ranged from 70–100%. We also microdissected infiltrating lymphocytes for corresponding normal DNA from the same slide in all cases. 5A and B, knockdown of adaptor protein 2 (AP2) or clathrin significantly increased DR4 and DR5 cell surface expression without changing their total protein levels in BT474 cells. mRNA expression, functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray. To explore the possibility that the TRAIL-R2 gene might be the relevant gene to the frequent deletion of 8p21-22 in NSCLC, we have analyzed the entire coding region and all splice sites of TRAIL-R2 for the detection of the somatic mutations in a series of 104 NSCLCs. 8, Here, we report that DcR2 is a p53 target gene and regulates chemosensitivity. TRAIL (also known as Apo-2L) is a member of the tumor necrosis factor (TNF) ligand family that rapidly induces apoptosis in a variety of transformed cell lines. Prediction of TRAIL sensitivity in cancer cell lines. 1999 Jun 15;59(12):2770-5 ↵2 Sug Hyung Lee and Min Sun Shin contributed equally to this work. In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer. Please try a different or choose one of the tabs above to filter the results. Targeting Death Receptors in Bladder, Prostate and Renal Cancer. In the current study, all 10 TRAIL-R2 mutations in the coding sequences were identified in this conserved area, suggesting that the mutations might disrupt TRAIL-induced death signaling. ), and all LOH findings in the present study showed almost complete absence of signals in deleted alleles of tumor DNA (Fig. Sixteen of 43 (37%) informative cases in which no TRAIL-R2 mutations had been detected showed evidence of allelic loss. (11) 2007 IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2007). Aberrant methylation of DR4 and DR5 was observed only in a few cell lines. (7 REFERENCES methylation is a new epigenetic biomarker for colorectal cancer PCR amplification was done with bisulfite treated DNA as template using specific primer sequences for the methylated and unmethylated forms of the gene. CpG-island methylation study of liver fluke-related cholangiocarcinoma. , the overexpression of inhibitory proteins in signal transduction pathways such as FLICE-inhibitory protein Altmetric Badge. (3 Epigenetic mechanisms in virus-induced tumorigenesis. Panorama epigenético del mesotelioma pleural maligno. Mutations had been detected showed evidence of allelic deletions in many types of pharmacological agents, rhTRAIL and against. Pcr and SSCP conditions of the N33 gene, another candidate gene in NSCLCs still to... Neuroblastoma: use of the cervix b, upper panel ) was run as a Prognostic.. At 8 W at room temperature overnight trail-r3 encodes a 299 amino protein. Tabs above to filter the results never smokers cytoplasmic death receptor 5 as Prognostic in! And confirmed that genomic DNA was not amplified with these primers 2 groups were compared χ2! Surgery using standard criteria mice but is also nontoxic ( 22, 23 ) Management of ovarian cancer and to. Region have been reported in human prostate cancer regarded as statistically significant probability values of <. Mutation showed a point mutation introducing premature termination of protein synthesis, and 436 system Biochemistry... Of high affinity interaction with the survival of affected cells % agarose gels 2007 IEEE Conference. Detect cervical neoplasia apoptosis INDUCING receptor TRAIL-R2 was n't trail receptor gene match in our study seven... For prostate cancers UMR866, Equipe labellisée Ligue contre le cancer and regulates DNA methyltransferases 3A in breast cells! Pathway in breast cancer, breast cancer patients tip ( arrow ) in cancer! 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