title: Vascular normalization by loss of Siah2 results in increased chemotherapeutic efficacy.
abstract: Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1α (Hif-1α). In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2(-/-) genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1α, expression of angiogenic factors was decreased in Siah2(-/-) tumors. Blood vessel normalization in Siah2(-/-) tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1α-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.
authors.affiliation: Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria, Australia.
authors.forename: Christina S F
authors.initials: CS
authors.lastname: Wong
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Sceneay
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.forename: Heloise M
authors.initials: HM
authors.lastname: Halse
authors.forename: Mira C P
authors.initials: MC
authors.lastname: Liu
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Titaina C U Potdevin
authors.initials: TC
authors.lastname: Hunnam
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Parker
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
mesh_terms: D000818:Animals; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases