This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xie, W. Articles by Reiss, M. Search for Related Content PubMed PubMed Citation Articles by Xie, W. Articles by Reiss, M.

Alterations of Smad Signaling in Human Breast Carcinoma Are Associated with Poor Outcome

A Tissue Microarray Study¹

Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903 [W. X., J. C. M., D. J. R., M. R.], and Departments of Pathology [D. L. R., R. L. C.] and Therapeutic Radiology [B. G. H.], and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

Based largely on studies of cell lines in vitro and of transgenic mouse models, disruptions of transforming growth factor (TGF) ß signaling are thought to contribute to the development and progression of human breast cancer. However, whether and how TGF-ß signaling becomes disrupted during human breast cancer development in vivo remains largely unknown. To address this question, we have compared the patterns of expression and activation of the postreceptor components of the TGF-ß signaling pathway, the so-called Smads, in human breast cancer cell lines with those in breast carcinoma specimens. None of the breast carcinoma cell lines were growth arrested by TGF-ß in vitro. Each of the tumor cell lines expressed normal levels of Smad2 and -3. Moreover, TGF-ß treatment induced phosphorylation of Smad2 (Smad2P) in each of these lines, except those that lacked TGF-ß type II receptors. Moreover, only one of the cell lines failed to express Smad4.

Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, Smad2P, as well as Smad4, indicating their ability to proliferate within a microenvironment that contains bioactive TGF-ß. Thirty cases (6.6%) failed to express Smad2P, suggesting the loss of TGF-ß receptor signaling. Nine cases (2%) failed to express Smad4, and 3 of these also failed to express Smad2P. Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression. Loss of Smad signaling was not associated with any particular histological subtype, histological or nuclear grade, estrogen- or progesterone receptor expression, or HER2/neu expression. Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases. Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival. Finally, analysis of a small cohort of hereditary breast cancers failed to reveal any association between BRCA1 or BRCA2 genotype and alterations in Smad signaling.

This article has been cited by other articles:

				W. Kong, H. Yang, L. He, J.-j. Zhao, D. Coppola, W. S. Dalton, and J. Q. Cheng MicroRNA-155 Is Regulated by the Transforming Growth Factor {beta}/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA Mol. Cell. Biol., November 15, 2008; 28(22): 6773 - 6784. [Abstract] [Full Text] [PDF]

				N. Kane, M. Jones, J. J. Brosens, P. T. K. Saunders, R. W. Kelly, and H. O. D. Critchley Transforming Growth Factor-{beta}1 Attenuates Expression of Both the Progesterone Receptor and Dickkopf in Differentiated Human Endometrial Stromal Cells Mol. Endocrinol., March 1, 2008; 22(3): 716 - 728. [Abstract] [Full Text] [PDF]

				D. Razanajaona, S. Joguet, A.-S. Ay, I. Treilleux, S. Goddard-Leon, L. Bartholin, and R. Rimokh Silencing of FLRG, an Antagonist of Activin, Inhibits Human Breast Tumor Cell Growth Cancer Res., August 1, 2007; 67(15): 7223 - 7229. [Abstract] [Full Text] [PDF]

				R. Ge, V. Rajeev, P. Ray, E. Lattime, S. Rittling, S. Medicherla, A. Protter, A. Murphy, J. Chakravarty, S. Dugar, et al. Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptor Kinase In vivo. Clin. Cancer Res., July 15, 2006; 12(14): 4315 - 4330. [Abstract] [Full Text] [PDF]

				Q. C. Lau, E. Raja, M. Salto-Tellez, Q. Liu, K. Ito, M. Inoue, T. C. Putti, M. Loh, T. K. Ko, C. Huang, et al. RUNX3 Is Frequently Inactivated by Dual Mechanisms of Protein Mislocalization and Promoter Hypermethylation in Breast Cancer. Cancer Res., July 1, 2006; 66(13): 6512 - 6520. [Abstract] [Full Text] [PDF]

				M. C Fleisch, C. A Maxwell, and M.-H. Barcellos-Hoff The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs. Endocr. Relat. Cancer, June 1, 2006; 13(2): 379 - 400. [Abstract] [Full Text] [PDF]

				J. E. Burdette, J. S. Jeruss, S. J. Kurley, E. J. Lee, and T. K. Woodruff Activin A Mediates Growth Inhibition and Cell Cycle Arrest through Smads in Human Breast Cancer Cells Cancer Res., September 1, 2005; 65(17): 7968 - 7975. [Abstract] [Full Text] [PDF]

				A. Shin, X.-O. Shu, Q. Cai, Y.-T. Gao, and W. Zheng Genetic Polymorphisms of the Transforming Growth Factor-{beta}1 Gene and Breast Cancer Risk: A Possible Dual Role at Different Cancer Stages Cancer Epidemiol. Biomarkers Prev., June 1, 2005; 14(6): 1567 - 1570. [Abstract] [Full Text] [PDF]

				J. M. Yingling and S. Glatt Impact of PK/PD Evaluation of Targeted Therapies on Early Drug Discovery and Clinical Development Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 227 - 230. [Full Text] [PDF]

				R. L. Elliott and G. C. Blobe Role of Transforming Growth Factor Beta in Human Cancer J. Clin. Oncol., March 20, 2005; 23(9): 2078 - 2093. [Abstract] [Full Text] [PDF]

				S.S. Prime, M. Davies, M. Pring, and I.C. Paterson THE ROLE OF TGF-{beta} IN EPITHELIAL MALIGNANCY AND ITS RELEVANCE TO THE PATHOGENESIS OF ORAL CANCER (PART II) Critical Reviews in Oral Biology & Medicine, November 1, 2004; 15(6): 337 - 347. [Abstract] [Full Text] [PDF]

				M. B. Buck, P. Fritz, J. Dippon, G. Zugmaier, and C. Knabbe Prognostic Significance of Transforming Growth Factor {beta} Receptor II in Estrogen Receptor-Negative Breast Cancer Patients Clin. Cancer Res., January 15, 2004; 10(2): 491 - 498. [Abstract] [Full Text] [PDF]

				M. A. Davis Making Mechanistic Connections between Cell Signaling Pathways and Pathological Endpoints Toxicol Pathol, January 1, 2004; 32(1_suppl): 131 - 135. [Abstract] [PDF]

				J. W. Mandell Phosphorylation State-Specific Antibodies: Applications in Investigative and Diagnostic Pathology Am. J. Pathol., November 1, 2003; 163(5): 1687 - 1698. [Abstract] [Full Text] [PDF]

				F. Zhang, M. Lundin, A. Ristimaki, P. Heikkila, J. Lundin, J. Isola, H. Joensuu, and M. Laiho Ski-related novel protein N (SnoN), a Negative Controller of Transforming Growth Factor-{beta} Signaling, Is a Prognostic Marker in Estrogen Receptor-positive Breast Carcinomas , Cancer Res., August 15, 2003; 63(16): 5005 - 5010. [Abstract] [Full Text] [PDF]

				J. S. Jeruss, C. D. Sturgis, A. W. Rademaker, and T. K. Woodruff Down-Regulation of Activin, Activin Receptors, and Smads in High-Grade Breast Cancer Cancer Res., July 1, 2003; 63(13): 3783 - 3790. [Abstract] [Full Text] [PDF]

				A. M. Dunning, P. D. Ellis, S. McBride, H. L Kirschenlohr, C. S. Healey, P. R. Kemp, R. N. Luben, J. Chang-Claude, A. Mannermaa, V. Kataja, et al. A Transforming Growth Factor{beta}1 Signal Peptide Variant Increases Secretion in Vitro and Is Associated with Increased Incidence of Invasive Breast Cancer Cancer Res., May 15, 2003; 63(10): 2610 - 2615. [Abstract] [Full Text] [PDF]

				Y. Li, X. Li, and F. H. Sarkar Gene Expression Profiles of I3C- and DIM-Treated PC3 Human Prostate Cancer Cells Determined by cDNA Microarray Analysis J. Nutr., April 1, 2003; 133(4): 1011 - 1019. [Abstract] [Full Text] [PDF]

				J. Xu, X. Luo, and N. Chegini Differential Expression, Regulation, and Induction of Smads, Transforming Growth Factor-{beta} Signal Transduction Pathway in Leiomyoma, and Myometrial Smooth Muscle Cells and Alteration by Gonadotropin-Releasing Hormone Analog J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1350 - 1361. [Abstract] [Full Text] [PDF]

				A K Banerjee, P H Rabbitts, and J George Lung cancer * 3: Fluorescence bronchoscopy: clinical dilemmas and research opportunities Thorax, March 1, 2003; 58(3): 266 - 271. [Abstract] [Full Text] [PDF]

				T. Sasaki, H. Suzuki, K. Yagi, M. Furuhashi, R. Yao, S. Susa, T. Noda, Y. Arai, K. Miyazono, and M. Kato Lymphoid Enhancer Factor 1 Makes Cells Resistant to Transforming Growth Factor {beta}-induced Repression of c-myc Cancer Res., February 15, 2003; 63(4): 801 - 806. [Abstract] [Full Text] [PDF]

				Y. Li and F. H. Sarkar Gene Expression Profiles of Genistein-Treated PC3 Prostate Cancer Cells J. Nutr., December 1, 2002; 132(12): 3623 - 3631. [Abstract] [Full Text] [PDF]

				L. Y. W. Bourguignon, P. A. Singleton, H. Zhu, and B. Zhou Hyaluronan Promotes Signaling Interaction between CD44 and the Transforming Growth Factor beta Receptor I in Metastatic Breast Tumor Cells J. Biol. Chem., October 11, 2002; 277(42): 39703 - 39712. [Abstract] [Full Text] [PDF]