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c-erbB-2 Related Aggressiveness in Breast Cancer Is Hypoxia Inducible Factor-1 Dependent

Departments of ¹ Pathology, ² Radiotherapy/Oncology, and ³ Surgery, Medical School, Democritus University of Thrace, Alexandroupolis, Greece; and ⁴ Nuffield Department of Clinical Laboratory Sciences and ⁵ Cancer Research United Kingdom, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

c-erbB-2–positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1 (HIF1) production (Laughner et al., Mol Cell Biol 2001;21:3995–4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1 expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2–positive and 90 c-erbB-2–negative carcinomas) were stained immunohistochemically for HIF1 and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1 protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1 expression. If activation of c-erbB-2 in humans results in overexpression of HIF1 independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2–positive breast tumors.

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