Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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-1α 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 T2-4 N0-1 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-1α 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-1α 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. © 2007 American Association for Cancer Research.

Original publication

DOI

10.1158/1078-0432.CCR-06-1266

Type

Journal article

Journal

Clinical Cancer Research

Publication Date

15/01/2007

Volume

13

Pages

550 - 558