Regulation of hepatocyte growth factor activator inhibitor 2 by hypoxia in breast cancer.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Generali
Daniele
D
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Fox
Stephen B
SB
Berruti
Alfredo
A
Moore
John W
JW
Brizzi
Maria Pia
MP
Patel
Nilay
N
Allevi
Giovanni
G
Bonardi
Simone
S
Aguggini
Sergio
S
Bersiga
Alessandra
A
Campo
Leticia
L
Dogliotti
Luigi
L
Bottini
Alberto
A
Harris
Adrian L
AL
D000951:Antigens, Neoplasm / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D008562:Membrane Glycoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C109148:SPINT2 protein, human; C089226:CA9 protein, human