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Matsuoka T, Yashiro M. The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers. Biomolecules 2023; 13:1551. [PMID: 37892233 PMCID: PMC10605301 DOI: 10.3390/biom13101551] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Transforming growth factor-β (TGF-β) has attracted attention as a tumor suppressor because of its potent growth-suppressive effect on epithelial cells. Dysregulation of the TGF-β signaling pathway is considered to be one of the key factors in carcinogenesis, and genetic alterations affecting TGF-β signaling are extraordinarily common in cancers of the gastrointestinal system, such as hereditary nonpolyposis colon cancer and pancreatic cancer. Accumulating evidence suggests that TGF-β is produced from various types of cells in the tumor microenvironment and mediates extracellular matrix deposition, tumor angiogenesis, the formation of CAFs, and suppression of the anti-tumor immune reaction. It is also being considered as a factor that promotes the malignant transformation of cancer, particularly the invasion and metastasis of cancer cells, including epithelial-mesenchymal transition. Therefore, elucidating the role of TGF-β signaling in carcinogenesis, cancer invasion, and metastasis will provide novel basic insight for diagnosis and prognosis and the development of new molecularly targeted therapies for gastrointestinal cancers. In this review, we outline an overview of the complex mechanisms and functions of TGF-β signaling. Furthermore, we discuss the therapeutic potentials of targeting the TGF-β signaling pathway for gastrointestinal cancer treatment and discuss the remaining challenges and future perspectives on targeting this pathway.
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Affiliation(s)
| | - Masakazu Yashiro
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka 5458585, Japan;
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2
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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3
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Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis. Oncogene 2013; 33:3473-84. [PMID: 23934187 DOI: 10.1038/onc.2013.300] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 06/10/2013] [Accepted: 06/17/2013] [Indexed: 12/31/2022]
Abstract
The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
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Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature. J Transl Med 2012; 92:883-95. [PMID: 22411066 PMCID: PMC3584162 DOI: 10.1038/labinvest.2012.47] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
SMAD proteins are downstream effectors of the TGF-β signaling pathway. Smad3-null mice develop colorectal cancer by 6 months of age. In this study, we have examined whether the loss of Smad3 promotes gastric neoplasia in mice. The stomachs of Smad3⁻/⁻ mice were compared with age-matched Smad3 heterozygous and wild-type mice. E-cadherin, Ki-67, phosphoSTAT3, and TFF2/SP expression was analyzed by immunohistochemisty. The short hairpin RNA (ShRNA)-mediated knockdown of Smad3 in AGS and MKN28 cells was also performed. In addition, we examined alterations in DCLK1-expressing cells. Smad3⁻/⁻ mouse stomachs at 6 months of age revealed the presence of exophytic growths along the lesser curvature in the proximal fundus. Six-month-old Smad3⁻/⁻ mouse stomachs showed metaplastic columnar glands initiating from the transition zone junction between the forestomach and the glandular epithelium along the lesser curvature. Ten-month-old Smad3⁻/⁻ mice all exhibited invasive gastric neoplastic changes with increased Ki-67, phosphoSTAT3 expression, and aberrant cytosolic E-cadherin staining in papillary glands within the invading submucosal gland. The shRNA-mediated knockdown of Smad3 in AGS and MKN28 cells promoted the expression of phosphoSTAT3. DCLK1-expressing cells, which also stained for the tuft cell marker acetylated-α-tubulin, were observed in 10-month-old Smad3⁻/⁻ mice within tumors and in fundic invasive lesions. In conclusion, Smad3-null mice develop gastric tumors in the fundus, which arise from the junction between the forestomach and the glandular epithelium and progress to prominent invasive tumors over time. Smad3-null mice represent a novel model of fundic gastric tumor initiated from forestomach/glandular transition zone along the lesser curvature.
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5
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Stock M, Otto F. Gene deregulation in gastric cancer. Gene 2005; 360:1-19. [PMID: 16154715 DOI: 10.1016/j.gene.2005.06.026] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Revised: 05/26/2005] [Accepted: 06/13/2005] [Indexed: 12/21/2022]
Abstract
Despite its decreasing frequency in the Western world during recent decades, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Due to the oligosymptomatic course of early gastric cancer, most cases are diagnosed in the advanced stages of the disease. The curative potential of current standard treatment continues to be unsatisfactory, despite multimodal approaches involving surgery, chemotherapy and radiotherapy. Novel therapeutics including small molecules and monoclonal antibodies are being developed and have been partially introduced into clinical use in connection with neoplastic diseases such as chronic myeloid leukemia, non-Hodgkin's lymphoma and colorectal cancer. Thorough understanding of the changes in gene expression occurring during gastric carcinogenesis may help to develop targeted therapies and improve the treatment of this disease. Novel molecular biology techniques have generated a wealth of data on up- and down-regulation, activation and inhibition of specific pathways in gastric cancer. Here, we provide an overview of the different aspects of aberrant gene expression patterns in gastric cancer.
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Affiliation(s)
- Michael Stock
- Department of Hematology and Oncology, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany
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Li X, Zhang YY, Wang Q, Fu SB. Association between endogenous gene expression and growth regulation induced by TGF-β1 in human gastric cancer cells. World J Gastroenterol 2005; 11:61-8. [PMID: 15609398 PMCID: PMC4205385 DOI: 10.3748/wjg.v11.i1.61] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between endogenous gene expression and growth regulation including proliferation and apoptosis induced by transforming growth factor-β1 (TGF-β1) in human gastric cancer (GC) cells.
METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the main components of the TGF-β1/Smads signal pathway in human poorly differentiated GC cell line BGC-823. Localization of Smad proteins was also determined using immunofluorescence. Then, the BGC-823 cells were cultured in the presence or absence of TGF-β1 (10 ng/mL) for 24 and 48 h, and the effects of TGF-β1 on proliferation and apoptosis were measured by cell growth curve and flow cytometry (FCM) analysis. The ultrastructural features of BGC-823 cells with or without TGF-β1 treatment were observed under transmission electron microscope. The apoptotic cells were visualized by means of the terminal deoxynucleotidyl transferase (TdT)-mediated dTUP in situ nick end-labeling (TUNEL) method. Meanwhile, the expression levels of endogenous p15,p21 and Smad7 mRNA and the corresponding proteins in the cells were detected at 1, 2 and 3 h after culture in the presence or absence of TGF-β1 (10 ng/mL) by semi-quantitative RT-PCR and Western blot, respectively.
RESULTS: The TGF-β1/Smad signaling was found to be intact and functional in BGC-823 cells. The growth curve revealed the most evident inhibition of cell proliferation by TGF-β1 at 48 h, and FCM assay showed G1 arrest accompanied with apoptosis induced by TGF-β1. The typical morphological changes of apoptosis were observed in cells exposed to TGF-β1. The apoptosis index (AI) in TGF-β1-treated cells was significantly higher than that in the untreated controls (10.7±1.3% vs 0.32±0.06%, P<0.01). The levels of p15,p21 and Smad7 mRNA and corresponding proteins in cells were significantly up-regulated at 1 h, but gradually returned to basal levels at 3 h following TGF-β1 (10 ng/mL) treatment.
CONCLUSION: TGF-β1 affects both proliferation and apoptosis of GC cells through the regulation of p15 and p21, and induces transient expression of Smad 7 as a negative feedback modulation of TGF-β1 signal. Our results suggest a novel functional role of p21 as an accelerant of TGF-β1-mediated apoptosis in GC cells.
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Affiliation(s)
- Xue Li
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
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Sjöblom T, Yakymovych I, Heldin CH, Ostman A, Souchelnytskyi S. Smad2 suppresses the growth of Mv1Lu cells subcutaneously inoculated in mice. Eur J Cancer 2004; 40:267-74. [PMID: 14728942 DOI: 10.1016/j.ejca.2003.08.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Smad2 and Smad3 are intracellular signal transduction proteins of importance in transforming growth factor-beta (TGFbeta)-mediated inhibition of epithelial cell proliferation. Inactivating mutations in the Smad2 and Smad3 genes have been found in various human malignancies. Here, we show that expression of Smad2 leads to the inhibition of growth of Mv1Lu cells inoculated with Matrigel subcutaneously (s.c.) in severe combined immunodeficient (SCID) mice. In histological appearance, the Matrigel plugs with Smad2-transfected cells showed strongly reduced cell density, proliferation and angiogenesis compared with the small tumour nodules of similar size formed by the vector- or Smad3-transfected cells. The histological appearance of vector- and Smad3-transfected cells inoculated in mice was identical. Overexpression of Smad2 and Smad3 in Mv1Lu cells led to the inhibition of cell growth in three-dimensional cultures when compared with vector-transfected cells. Overexpression of Smad2 and Smad3 also decreased the hyperphosphorylation of pRb in Smad-transfected cells. Thus, increased expression of Smad2 leads to inhibition of Mv1Lu cell proliferation and a reduction in the growth of the Smad2-expressing cells inoculated in mice.
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Affiliation(s)
- T Sjöblom
- Ludwig Institute for Cancer Research, Box 595, SE-751 24, Uppsala, Sweden
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Han SU, Kim HT, Seong DH, Kim YS, Park YS, Bang YJ, Yang HK, Kim SJ. Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene 2004; 23:1333-1341. [PMID: 14647420 DOI: 10.1038/sj.onc.1207259] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2003] [Revised: 10/01/2003] [Accepted: 10/03/2003] [Indexed: 12/16/2022]
Abstract
Loss of the tumor suppressive effect of transforming growth factor-beta (TGF-beta) has been commonly found at later stages in carcinogenic progression. Although the genes encoding TGF-beta receptors and Smads have been found genetically altered in certain human cancers, no mutation in Smad3 has been observed. Therefore, suppression of Smad3 expression may mediate key oncogenic properties of TGF-beta. First, we observed that 37.5% of human gastric cancer tissues showed low to undetectable levels of Smad3 and that in nine human gastric cancer cell lines examined, two showed deficient Smad3 expression. Introduction of Smad3 into human gastric cancer cells that did not express Smad3, restored TGF-beta responsiveness: induction of p21 and p15 gene expression, and growth inhibition in response to TGF-beta. Furthermore, these Smad3-expressing cells showed markedly decreased and delayed tumorigenicity in vivo. These findings suggest that Smad3 expression may have a critical role in tumor suppression in the early stages of gastric carcinogenesis.
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Affiliation(s)
- Sang-Uk Han
- Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055, USA
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9
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Candusso ME, Luinetti O, Villani L, Alberizzi P, Klersy C, Fiocca R, Ranzani GN, Solcia E. Loss of heterozygosity at 18q21 region in gastric cancer involves a number of cancer-related genes and correlates with stage and histology, but lacks independent prognostic value. J Pathol 2002; 197:44-50. [PMID: 12081203 DOI: 10.1002/path.1105] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Several studies support a role of 18q21 LOH, involving the DCC locus, in colorectal cancer progression; however, its contribution to the natural history of gastric cancer is less clear. Recently, a number of cancer-related genes have been mapped in the 18q21 region, either centromeric or telomeric to DCC. This study searched for 18q21 LOH in 161 gastric cancers representative of all tumour stages and main histological types. To this purpose, seven highly polymorphic markers were used flanking the 18q21 band and spanning the entire region. Thirty-four out of 147 (23.1%) informative cases showed LOH. In 27 of 34 cases (79%), LOH involved all the informative loci. The remaining seven cases showed LOH at more telomeric sites and retained heterozygosity at more centromeric markers, mostly those proximal to the DCC gene. A strong correlation between 18q21 LOH and level of gastric wall invasion, lymph node metastases, or stage was found in cohesive (glandular+solid) and mixed tumours, but not in diffuse cancers. Cox univariate and multivariate analysis showed that invasion level, lymph node metastases, distant metastases, TNM stage, and histology were effective predictors of survival, whereas 18q21 LOH did not show predictive power. The simultaneous deletion of a variety of cancer-related genes with different and even opposite roles might explain why, apparently, 18q21 LOH does not per se contribute significantly to the natural history of gastric cancer, despite strong correlation with stage.
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Affiliation(s)
- M E Candusso
- Department of Pathology, IRCCS Policlinico San Matteo and University of Pavia, Italy
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Yokozaki H, Yasui W, Tahara E. Genetic and epigenetic changes in stomach cancer. INTERNATIONAL REVIEW OF CYTOLOGY 2001; 204:49-95. [PMID: 11243597 DOI: 10.1016/s0074-7696(01)04003-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Genetic and epigenetic alterations of multiple cancer-related genes and molecules are implicated in the development and progression of human gastric carcinomas. Reactivation of telomerase, inactivation of p53 tumor suppressor gene, overexpression of cyclin E, and reduced expression of p27 KIP1 by disorganized degradation in proteasome are common events of both well-differentiated and poorly differentiated gastric adenocarcinomas. Inactivation of hMLH1 mismatch repair gene by CpG hypermethylation resulting in microsatellite instability, amplification of c-erbB2 oncogene, inactivation of APC tumor suppressor gene, and K-ras mutations are preferentially associated with well-differentiated gastric cancer. Conversely, reduction or loss of E-cadherin and catenins by both mutation and CpG hypermethylation and K-sam and c-met oncogene amplification are necessary for the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cancer cells expressing c-met and hepatocyte growth factor from stromal cells is implicated in morphogenesis of gastric cancer.
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Affiliation(s)
- H Yokozaki
- First Department of Pathology, Hiroshima University School of Medicine, Japan
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Abstract
Molecular characterization of eight gastric cancer cell lines established in Japan are summarized according to the genetic and epigenetic alterations and growth factor status. TMK-1 poorly differentiated adenocarcinoma cell line harbors mutant p53 tumor suppressor gene and rearrangement of p15MTS2. MKN-1 adenosquamous carcinoma line with mutant p53 reveals silencing of E-cadherin by promoter CpG hypermethylation. MKN-7 well-differentiated adenocarcinoma cell line has amplification of c-erbB2 oncogene and cyclin E gene. MKN-28 well-differentiated adenocarcinoma cell line reveals mutations in p53 and APC tumor suppressor genes and silencing of CD44. The MKN-45 poorly differentiated adenocarcinoma cell line with wild-type p53 is characterized by homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplification of c-met oncogene and promoter mutation of E-cadherin. MKN-74 derived from moderately differentiated tubular adenocarcinoma has wild-type p53. KATO-III signet ring cell carcinoma line has genomic deletion of p53, amplification of K-sam and c-met oncogene and mutation of E-cadherin. HSC-39 signet ring cell carcinoma cell line harboring p53 missense mutation has homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplifications of c-myc, c-met, K-sam and CD44 gene and mutation in beta-catenin gene.
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Affiliation(s)
- H Yokozaki
- First Department of Pathology, Hiroshima University School of Medicine, Hiroshima, Japan.
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Kretzschmar M. Transforming growth factor-beta and breast cancer: Transforming growth factor-beta/SMAD signaling defects and cancer. Breast Cancer Res 2000; 2:107-15. [PMID: 11250700 PMCID: PMC139432 DOI: 10.1186/bcr42] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/1999] [Revised: 01/25/2000] [Accepted: 01/26/2000] [Indexed: 01/30/2023] Open
Abstract
Transforming growth factor-beta (TGF-beta) is a tumor suppressor, the function of which is compromised in many types of human cancer, including breast cancer. The tumor suppressive effects of TGF-beta are caused by potent inhibition of cell proliferation due to cell cycle arrest in the G1 phase. Such antiproliferative responses are mediated by a signaling system that includes two types of cell surface receptors and intracellular signal transducers, the SMAD proteins. Different molecular mechanisms can lead to loss of antiproliferative TGF-beta responses in tumor cells, including mutations in components of the signaling system and inhibition of the SMAD signaling pathway by aberrant activities of various regulatory molecules. Some of these mechanisms will be discussed, with emphasis on their potential involvement in breast tumorigenesis.
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Affiliation(s)
- M Kretzschmar
- Ruttenberg Cancer Center, NYU-Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
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