Abstract | PURPOSE: MATERIALS AND METHODS: HAI-2 regulation was studied in a panel of breast cancer cell lines comparing normoxia to hypoxia. The effect of HIF-1alpha RNAi on HAI-2 expression was evaluated in these cells. HAI-2 was examined in breast cancer using in situ hybridization and immunohistochemistry. The HAI-2 predictive role was assessed in T(2-4) N(0-1) breast cancers (n = 177) enrolled in a neoadjuvant randomized trial comparing epirubicin versus epirubicin + tamoxifen. RESULTS: HAI-2 mRNA and protein were regulated by hypoxia in the c-erbB2-positive cell lines, SKBR3 and BT474, and controlled by HIF-1alpha in these cells. Immunohistochemistry confirmed this profile with high expression of HAI-2 in c-erbB2-positive breast cancer. HAI-2 was correlated with T status (P < 0.004), node involvement (P = 0.01), and c-erbB2 expression (P = 0.05). HAI-2 also correlated with hypoxia markers such as carbonic anhydrase IX expression (P = 0.01) and HIF-1alpha. Additionally, high levels of HAI-2 were a significant predictor for poor clinical complete response to preoperative epirubicin in univariate (P = 0.01) and multivariate analyses (P = 0.016). No correlation with disease-free survival and survival was observed. CONCLUSION: HAI-2 expression in breast cancer correlated with tumor aggressiveness in vivo. It is a HIF target in c-erbB2-positive cells and it is an independent negative predictive factor of efficacy of anthracycline therapy. The interaction of HAI-2 with the hepatocyte growth factor activation pathway may be a useful site for therapeutic intervention.
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Authors | Daniele Generali, Stephen B Fox, Alfredo Berruti, John W Moore, Maria Pia Brizzi, Nilay Patel, Giovanni Allevi, Simone Bonardi, Sergio Aguggini, Alessandra Bersiga, Leticia Campo, Luigi Dogliotti, Alberto Bottini, Adrian L Harris |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 2 Pt 1
Pg. 550-8
(Jan 15 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17255277
(Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, Neoplasm
- Membrane Glycoproteins
- SPINT2 protein, human
- Receptor, ErbB-2
- CA9 protein, human
- Carbonic Anhydrase IX
- Carbonic Anhydrases
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Topics |
- Antigens, Neoplasm
(biosynthesis)
- Breast Neoplasms
(enzymology, pathology)
- Carbonic Anhydrase IX
- Carbonic Anhydrases
(biosynthesis)
- Cell Line, Tumor
- Disease-Free Survival
- Female
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia
- Immunohistochemistry
- In Situ Hybridization
- Membrane Glycoproteins
(metabolism)
- RNA Interference
- Receptor, ErbB-2
(biosynthesis)
- Up-Regulation
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