This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this book Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Negro, A. Articles by Lee, K.-F. Search for Related Content PubMed PubMed Citation Articles by Negro, A. Articles by Lee, K.-F.

Essential Roles of Her2/erbB2 in Cardiac Development and Function

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037-1002

The tyrosine kinase receptor erbB2, also known in humans as Her2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family, which also includes erbB3 and erbB4. The erbBs were discovered in an avian erythroblastosis tumor virus and exhibited similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2 is highly expressed in many cancer types. Its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. ErbB receptors bind to a family of growth factors, termed neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4 and include multiple isoforms. ErbB2/Her2 is an orphan receptor that does not bind ligand alone but heterodimerizes with the other erbB receptors for NRG signaling. ErbB2 is expressed in multiple neuronal and non-neuronal tissues in embryos and adult animals, including the heart. Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die before embryonic day (E) 11. To study its role at later stages of development, we generated a transgenic mouse line that specifically expresses the rat erbB2 cDNA in the heart under the control of the cardiac-specific -myosin heavy chain promoter. When crossed into the null background, the expression of the rat erbB2 cDNA rescued the cardiac phenotype in the erbB2-null mutant mice that survive until birth but display an absence of Schwann cells and a severe loss of both motor and spinal sensory neurons. To study the role of erbB2 in the adult heart, we generated conditional mutant mice carrying a cardiac-restricted deletion of erbB2. These erbB2 conditional mutants exhibited multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Interestingly, treatment of breast cancers overexpressing erbB2 with Herceptin (Trastuzumab), a humanized monoclonal antibody specific to the extracellular domain of erbB2, results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. We found that erbB2-deficient cardiac myocytes are more susceptible to anthracycline-induced cytotoxicity. These results suggest that erbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. These lines of mice provide models with which to elucidate the molecular and cellular mechanisms by which erbB2 signaling regulates cardiac functions. These mice also will provide important information for devising strategies to mitigate the cardiotoxic effects of Herceptin treatment, allowing for the potential expanded use of this drug to treat all cancers overexpressing erbB2.

This article has been cited by other articles:

				S. M. Swain, M. S. Ewer, J. Cortes, D. Amadori, D. Miles, A. Knott, E. Clark, M. C. Benyunes, G. Ross, and J. Baselga Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer in CLEOPATRA: A Randomized, Double-Blind, Placebo-Controlled Phase III Study Oncologist, March 1, 2013; 18(3): 257 - 264. [Abstract] [Full Text] [PDF]

				K. W. Turteltaub, M. A. Davis, L. A. Burns-Naas, M. P. Lawton, A. M. Clark, and J. A. Reynolds Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine Clin. Cancer Res., November 1, 2011; 17(21): 6641 - 6645. [Abstract] [Full Text] [PDF]

				N. Verma and S. M. Swain Bevacizumab and Heart Failure Risk in Patients With Breast Cancer: A Thorn in the Side? J. Clin. Oncol., February 20, 2011; 29(6): 603 - 606. [Full Text] [PDF]

				L. Tookman and R. Roylance New drugs for breast cancer Br. Med. Bull., December 1, 2010; 96(1): 111 - 129. [Abstract] [Full Text] [PDF]

				A. Bollig-Fischer, M. Dziubinski, A. Boyer, R. Haddad, C. N. Giroux, and S. P. Ethier HER-2 Signaling, Acquisition of Growth Factor Independence, and Regulation of Biological Networks Associated with Cell Transformation Cancer Res., October 15, 2010; 70(20): 7862 - 7873. [Abstract] [Full Text] [PDF]

				T. A. Yap, L. Vidal, J. Adam, P. Stephens, J. Spicer, H. Shaw, J. Ang, G. Temple, S. Bell, M. Shahidi, et al. Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors J. Clin. Oncol., September 1, 2010; 28(25): 3965 - 3972. [Abstract] [Full Text] [PDF]

				Y. Bian, M. Sun, M. Silver, K. K. L. Ho, M. A. Marchionni, A. O. Caggiano, J. R. Stone, I. Amende, T. G. Hampton, J. P. Morgan, et al. Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H1974 - H1983. [Abstract] [Full Text] [PDF]

				K. E. Tifft, K. A. Bradbury, and K. L. Wilson Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases J. Cell Sci., October 15, 2009; 122(20): 3780 - 3790. [Abstract] [Full Text] [PDF]

				R. M. Esper and J. A. Loeb Neurotrophins Induce Neuregulin Release through Protein Kinase C{delta} Activation J. Biol. Chem., September 25, 2009; 284(39): 26251 - 26260. [Abstract] [Full Text] [PDF]

				T. A. Prokhorova, K. T. G. Rigbolt, P. T. Johansen, J. Henningsen, I. Kratchmarova, M. Kassem, and B. Blagoev Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Quantitative Comparison of the Membrane Proteomes of Self-renewing and Differentiating Human Embryonic Stem Cells Mol. Cell. Proteomics, May 1, 2009; 8(5): 959 - 970. [Abstract] [Full Text] [PDF]

				G. Hua, B. Zhu, F. Rosa, N. Deblon, J. Adelaide, B. Kahn-Perles, D. Birnbaum, and J. Imbert A Negative Feedback Regulatory Loop Associates the Tyrosine Kinase Receptor ERBB2 and the Transcription Factor GATA4 in Breast Cancer Cells Mol. Cancer Res., March 1, 2009; 7(3): 402 - 414. [Abstract] [Full Text] [PDF]

				S. Pant, M. B. Landon, M. Blumenfeld, W. Farrar, and C. L. Shapiro Treatment of Breast Cancer With Trastuzumab During Pregnancy J. Clin. Oncol., March 20, 2008; 26(9): 1567 - 1569. [Full Text] [PDF]

				A. Ramond, E. Sartorius, M. Mousseau, C. Ribuot, and M. Joyeux-Faure Erythropoietin Pretreatment Protects Against Acute Chemotherapy Toxicity in Isolated Rat Hearts Exp Biol Med, January 1, 2008; 233(1): 76 - 83. [Abstract] [Full Text] [PDF]

				K. Y. Chung and J. W. Walker Interaction and Inhibitory Cross-Talk between Endothelin and ErbB Receptors in the Adult Heart Mol. Pharmacol., June 1, 2007; 71(6): 1494 - 1502. [Abstract] [Full Text] [PDF]

				D. B. Agus, C. J. Sweeney, M. J. Morris, D. S. Mendelson, D. G. McNeel, F. R. Ahmann, J. Wang, M. K. Derynck, K. Ng, B. Lyons, et al. Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy J. Clin. Oncol., February 20, 2007; 25(6): 675 - 681. [Abstract] [Full Text] [PDF]

				J. S. de Bono, J. Bellmunt, G. Attard, J. P. Droz, K. Miller, A. Flechon, C. Sternberg, C. Parker, G. Zugmaier, V. Hersberger-Gimenez, et al. Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer J. Clin. Oncol., January 20, 2007; 25(3): 257 - 262. [Abstract] [Full Text] [PDF]

				V. Tolmachev, F. Y. Nilsson, C. Widstrom, K. Andersson, D. Rosik, L. Gedda, A. Wennborg, and A. Orlova 111In-Benzyl-DTPA-ZHER2:342, an Affibody-Based Conjugate for In Vivo Imaging of HER2 Expression in Malignant Tumors J. Nucl. Med., May 1, 2006; 47(5): 846 - 853. [Abstract] [Full Text] [PDF]

				M. N. Levine Trastuzumab Cardiac Side Effects: Only Time Will Tell J. Clin. Oncol., November 1, 2005; 23(31): 7775 - 7776. [Full Text] [PDF]

				Y. P. Hu, S. Venkateswarlu, N. Sergina, G. Howell, P. St. Clair, L. E. Humphrey, W. Li, J. Hauser, E. Zborowska, J. K. V. Willson, et al. Reorganization of ErbB Family and Cell Survival Signaling after Knock-down of ErbB2 in Colon Cancer Cells J. Biol. Chem., July 22, 2005; 280(29): 27383 - 27392. [Abstract] [Full Text] [PDF]

				D. E. Nethery, B. B. Moore, G. Minowada, J. Carroll, J. A. Faress, and J. A. Kern Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice J Appl Physiol, July 1, 2005; 99(1): 298 - 307. [Abstract] [Full Text] [PDF]

				C.-L. Cai, W. Zhou, L. Yang, L. Bu, Y. Qyang, X. Zhang, X. Li, M. G. Rosenfeld, J. Chen, and S. Evans T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis Development, May 15, 2005; 132(10): 2475 - 2487. [Abstract] [Full Text] [PDF]

				M. S. Ewer and S. M. Lippman Type II Chemotherapy-Related Cardiac Dysfunction: Time to Recognize a New Entity J. Clin. Oncol., May 1, 2005; 23(13): 2900 - 2902. [Full Text] [PDF]