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Regulation of Hepatocyte Growth Factor Activator Inhibitor 2 by Hypoxia in Breast Cancer

Authors' Affiliations: ¹ Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; ² Department of Pathology, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia; ³ Unità di Patologia Mammaria-Breast Cancer Unit, ⁴ Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; and ⁵ Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Azienda Ospedaliera San Luigi di Orbassano, Orbassano, Italy

Requests for reprints: Adrian L. Harris, Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, United Kingdom. Phone: 44-1865-222-457; Fax: 44-1865-222-431; E-mail: aharris.lab{at}cancer.org.uk.

Purpose: To examine the in vitro regulation of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in breast cancer cells and the in vivo predictive role for the efficacy of chemoendocrine primary therapy in patients with breast cancer.

Materials and Methods: HAI-2 regulation was studied in a panel of breast cancer cell lines comparing normoxia to hypoxia. The effect of HIF-1 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-1 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-1. 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.