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BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1 pathway and prognosis

¹ Departments of Pathology, and Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece
² Department of Pathology, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DS, UK
³ Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 7LJ, UK

Correspondence to:
Alexandra Giatromanolaki, MD, Department of Pathology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece; targ{at}her.forthnet.gr

Aims: BNIP3 is a pro-apoptotic mitochondrial protein induced under hypoxic stress, with the BNIP3 gene being under direct regulation of the hypoxia-inducible HIF-1 transcription factor. Induction of BNIP3 leads to caspase-independent necrosis-like cell death and an aggressive tumour phenotype. The role of BNIP3 in endometrial cancer was examined.

Methods: The immunohistochemical patterns of BNIP3 expression in 72 early endometrial adenocarcinomas of the endometrioid cell type were studied. Correlation of BNIP3 with the hypoxia-inducible factor HIF-1 pathway and with prognosis was also examined.

Results: BNIP3 was strongly and extensively expressed in the cytoplasm of cancer cells in 23/72 (31.9%) cases. This high BNIP3 reactivity was not related to histological grade, depth of myometrial invasion or steroid hormone receptor expression. There was, however, a significant association of BNIP3 reactivity with HIF-1 (p = 0.04), VEGF (p = 0.04) and, particularly, LDH-5 expression (p = 0.0001). Furthermore, high BNIP3 was associated with poor survival in both univariate (p = 0.05) and multivariate (p = 0.03) models.

Conclusion: BNIP3 seems to be an important hypoxia-regulated molecule involved in endometrial cancer pathology. Given that high BNIP3 reactivity, being linked with poor post-operative outcome, has been linked with a favourable response to cytotoxic therapy (as previously indicated in experimental studies), high BNIP3 expression may be an indicator for adjuvant chemoradiotherapy in stage I endometrial carcinomas.

Keywords: endometrial cancer; BNIP3; HIF1; LDH-5; prognosis