title: Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer.
abstract: 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 co-dependency between HAS2, CD44, and HYAL2 expression.
authors: Laboratory for Hyaluronan Research, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors: Lishanthi
authors: L
authors: Udabage
authors: Gary R
authors: GR
authors: Brownlee
authors: Mark
authors: M
authors: Waltham
authors: Tony
authors: T
authors: Blick
authors: Emma C
authors: EC
authors: Walker
authors: Paraskevi
authors: P
authors: Heldin
authors: Susan K
authors: SK
authors: Nilsson
authors: Erik W
authors: EW
authors: Thompson
authors: Tracey J
authors: TJ
authors: Brown
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D016193:G1 Phase / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D014162:Transfection
chemical_list: D016373:DNA, Antisense; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases