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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Wong CS,Sceneay J,House CM,Halse HM,Liu MC,George J,Hunnam TC,Parker BS,Haviv I,Ronai Z,Cullinane C,Bowtell DD,Möller Adoi
10.1158/0008-5472.CAN-11-3310subject
Has Abstractpub_date
2012-04-01 00:00:00pages
1694-704issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-11-3310journal_volume
72pub_type
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