This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Udabage, L. Articles by Brown, T. J. Search for Related Content PubMed PubMed Citation Articles by Udabage, L. Articles by Brown, T. J.

Antisense-Mediated Suppression of Hyaluronan Synthase 2 Inhibits the Tumorigenesis and Progression of Breast Cancer

¹ Laboratory for Hyaluronan Research, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia; ² St. Vincent's Institute of Medical Research, Melbourne, Australia; ³ Department of Medical Biochemistry and Microbiology, Ludwig Institute for Cancer Research, Uppsala, Sweden; and ⁴ Stem Cell Laboratory, Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, Australia

Requests for reprints: Tracey Brown, Laboratory for Hyaluronan Research, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Monash University, Wellington Road, Clayton, Victoria 3800, Australia. Phone: 61-3-9905-3760; Fax: 61-3-9905-3726; E-mail: tracy.brown{at}med.monash.edu.au.

The progression of several cancers is correlated with the increased synthesis of the glycosaminoglycan, hyaluronan. Hyaluronan is synthesized at the plasma membrane by various isoforms of hyaluronan synthases (HAS). The importance of HAS2 expression in highly invasive breast cancer was characterized by the antisense inhibition of HAS2 (ASHAS2). The effect of HAS2 inhibition on cell proliferation, migration, hyaluronan metabolism, and receptor status was characterized in vitro, whereas the effect on tumorigenicity and metastasis was established in vivo. HAS2 inhibition resulted in a 24-hour lag in proliferation that was concomitant to transient arrest of 79% of the cell population in G₀-G₁. Inhibition of HAS2 did not alter the expression of the other HAS isoforms, whereas hyaluronidase (HYAL2) and the hyaluronan receptor, CD44, were significantly down-regulated. ASHAS2 cells accumulated greater amounts of high molecular weight hyaluronan (>10,000 kDa) in the culture medium, whereas mock and parental cells liberated less hyaluronan of three distinct molecular weights (100, 400, and 3,000 kDa). The inhibition of HAS2 in the highly invasive MDA-MB-231 breast cancer cell line inhibited the initiation and progression of primary and secondary tumor formation following s.c. and intracardiac inoculation into nude mice, whereas controls readily established both primary and secondary tumors. The lack of primary and secondary tumor formation was manifested by increased survival times where ASHAS2 animals survived 172% longer than the control animals. Collectively, these unique results strongly implicate the central role of HAS2 in the initiation and progression of breast cancer, potentially highlighting the codependency between HAS2, CD44, and HYAL2 expression.

This article has been cited by other articles:

				L. C. Becker, W. F. Bergfeld, D. V. Belsito, C. D. Klaassen, J. G. Marks Jr, R. C. Shank, T. J. Slaga, P. W. Snyder, Cosmetic Ingredient Review Expert Panel, and F. A. Andersen Final Report of the Safety Assessment of Hyaluronic Acid, Potassium Hyaluronate, and Sodium Hyaluronate International Journal of Toxicology, July 1, 2009; 28(4_suppl): 5 - 67. [Abstract] [Full Text] [PDF]

				Y. Kim, Y.-S. Lee, J. Choe, H. Lee, Y.-M. Kim, and D. Jeoung CD44-Epidermal Growth Factor Receptor Interaction Mediates Hyaluronic Acid-promoted Cell Motility by Activating Protein Kinase C Signaling Involving Akt, Rac1, Phox, Reactive Oxygen Species, Focal Adhesion Kinase, and MMP-2 J. Biol. Chem., August 15, 2008; 283(33): 22513 - 22528. [Abstract] [Full Text] [PDF]

				X. Li, S. L Nott, Y. Huang, R. Hilf, R. A Bambara, X. Qiu, A. Yakovlev, S. Welle, and M. Muyan Gene expression profiling reveals that the regulation of estrogen-responsive element-independent genes by 17{beta}-estradiol-estrogen receptor {beta} is uncoupled from the induction of phenotypic changes in cell models J. Mol. Endocrinol., May 1, 2008; 40(5): 211 - 229. [Abstract] [Full Text] [PDF]

				R. Golshani, L. Lopez, V. Estrella, M. Kramer, N. Iida, and V. B. Lokeshwar Hyaluronic Acid Synthase-1 Expression Regulates Bladder Cancer Growth, Invasion, and Angiogenesis through CD44 Cancer Res., January 15, 2008; 68(2): 483 - 491. [Abstract] [Full Text] [PDF]

				D.-M. Kuang, Y. Wu, N. Chen, J. Cheng, S.-M. Zhuang, and L. Zheng Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes Blood, July 15, 2007; 110(2): 587 - 595. [Abstract] [Full Text] [PDF]

				A. G. Bharadwaj, K. Rector, and M. A. Simpson Inducible Hyaluronan Production Reveals Differential Effects on Prostate Tumor Cell Growth and Tumor Angiogenesis J. Biol. Chem., July 13, 2007; 282(28): 20561 - 20572. [Abstract] [Full Text] [PDF]

				L. Y. W. Bourguignon, E. Gilad, and K. Peyrollier Heregulin-mediated ErbB2-ERK Signaling Activates Hyaluronan Synthases Leading to CD44-dependent Ovarian Tumor Cell Growth and Migration J. Biol. Chem., July 6, 2007; 282(27): 19426 - 19441. [Abstract] [Full Text] [PDF]

				S. R. Hamilton, S. F. Fard, F. F. Paiwand, C. Tolg, M. Veiseh, C. Wang, J. B. McCarthy, M. J. Bissell, J. Koropatnick, and E. A. Turley The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells J. Biol. Chem., June 1, 2007; 282(22): 16667 - 16680. [Abstract] [Full Text] [PDF]

				S. M. Gallagher, J. J. Castorino, D. Wang, and N. J. Philp Monocarboxylate Transporter 4 Regulates Maturation and Trafficking of CD147 to the Plasma Membrane in the Metastatic Breast Cancer Cell Line MDA-MB-231 Cancer Res., May 1, 2007; 67(9): 4182 - 4189. [Abstract] [Full Text] [PDF]

				C. L. Chaffer, J. P. Brennan, J. L. Slavin, T. Blick, E. W. Thompson, and E. D. Williams Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2 Cancer Res., December 1, 2006; 66(23): 11271 - 11278. [Abstract] [Full Text] [PDF]

				M. Gotte and G. W. Yip Heparanase, Hyaluronan, and CD44 in Cancers: A Breast Carcinoma Perspective Cancer Res., November 1, 2006; 66(21): 10233 - 10237. [Abstract] [Full Text] [PDF]

				L. Li, C.-H. Heldin, and P. Heldin Inhibition of Platelet-derived Growth Factor-BB-induced Receptor Activation and Fibroblast Migration by Hyaluronan Activation of CD44 J. Biol. Chem., September 8, 2006; 281(36): 26512 - 26519. [Abstract] [Full Text] [PDF]

				G. W. Yip, M. Smollich, and M. Gotte Therapeutic value of glycosaminoglycans in cancer. Mol. Cancer Ther., September 1, 2006; 5(9): 2139 - 2148. [Abstract] [Full Text] [PDF]

				A. C. Cook, A. F. Chambers, E. A. Turley, and A. B. Tuck Osteopontin Induction of Hyaluronan Synthase 2 Expression Promotes Breast Cancer Malignancy J. Biol. Chem., August 25, 2006; 281(34): 24381 - 24389. [Abstract] [Full Text] [PDF]

				M. A. Simpson Concurrent Expression of Hyaluronan Biosynthetic and Processing Enzymes Promotes Growth and Vascularization of Prostate Tumors in Mice Am. J. Pathol., July 1, 2006; 169(1): 247 - 257. [Abstract] [Full Text] [PDF]